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Shi J, Liu X, Gao M, Yu J, Chai T, Jiang Y, Li J, Zhang Y, Wu L. Adverse event profiles of EGFR-TKI: network meta-analysis and disproportionality analysis of the FAERS database. Front Pharmacol 2025; 16:1519849. [PMID: 40135231 PMCID: PMC11933087 DOI: 10.3389/fphar.2025.1519849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Accepted: 02/17/2025] [Indexed: 03/27/2025] Open
Abstract
Background Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR-TKIs) in clinical use show promise but can cause AEs, impacting patients' wellbeing and increasing costs. Methods This study utilized two methods: network meta-analysis (NMA) and disproportionality analysis (DA). For NMA, we searched PubMed, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov up to 10 September 2024, for phase II/III RCTs comparing EGFR-TKI monotherapy with chemotherapy or other EGFR-TKIs. Using STATA 18.0, we calculated odds ratios (ORs) with 95% confidence intervals (CIs) and assessed heterogeneity via Chi-squared and I2 tests. Adverse events (AEs) were ranked using the surface under the cumulative ranking curve (SUCRA). For DA, we analyzed FAERS data (January 2004-June 2024), evaluating AE signals with reporting odds ratios (RORs) and 95% CIs; signals were considered significant if the ROR and its 95% CI lower bound exceeded 1. Primary outcomes for NMA included all-grade AEs, grade ≥3 AEs, specific AEs, and AE-related mortality. For DA, outcomes included EGFR-TKI as the primary AE cause, time from treatment to AE, and AE-related mortality. Results NMA: 48% of EGFR-TKI patients experienced AEs, with 32.7% being severe. Afatinib showed highest toxicity; Icotinib was safest. Osimertinib was associated with highest risks of leukopenia (8%) and thrombocytopenia (9%). DA: Osimertinib had strongest links to cardiac diseases and blood/lymphatic disorders. Gefitinib had the strongest signal for interstitial lung diseases; Erlotinib for anorexia. Most AEs occurred within 30 days, but cardiac disorders had a median onset of 41 days. Osimertinib had the highest AE-related mortality, with cardiac disorders leading in fatalities. Conclusion This study used NMA and DA to explore EGFR-TKI-related AEs. Drugs varied in AE profiles, mostly mild, but Osimertinib and Dacomitinib were associated with more severe events. Osimertinib carried a high cardiac risk, delayed onset, and high mortality. Thus, comprehensive patient assessment and close monitoring are crucial with EGFR-TKI use.
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Affiliation(s)
- Jing Shi
- Xinjiang Medical University, Urumqi, China
- Department of Oncology Cardiology, Affiliated Cancer Hospital of Xinjiang Medical University, Urumqi, China
| | - Xinya Liu
- Xinjiang Medical University, Urumqi, China
- The Fifth Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Mengjiao Gao
- Department of Oncology Cardiology, Affiliated Cancer Hospital of Xinjiang Medical University, Urumqi, China
| | - Jian Yu
- Xinjiang Medical University, Urumqi, China
| | - Ting Chai
- Department of Oncology Cardiology, Xinjiang Cardiovascular and Cerebrovascular Hospital, Urumqi, China
| | - Yun Jiang
- Department of Oncology Cardiology, Affiliated Cancer Hospital of Xinjiang Medical University, Urumqi, China
| | - Jiawei Li
- Department of Oncology Cardiology, Affiliated Cancer Hospital of Xinjiang Medical University, Urumqi, China
| | - Yuanming Zhang
- Department of Oncology Cardiology, Affiliated Cancer Hospital of Xinjiang Medical University, Urumqi, China
| | - Li Wu
- Department of Oncology Cardiology, Affiliated Cancer Hospital of Xinjiang Medical University, Urumqi, China
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Bhagyalalitha M, Handattu Shankaranarayana A, Arun Kumar S, Singh M, Pujar KG, Bidye D, Veeranna Pujar G. Advances in HER2-Targeted Therapies: From monoclonal antibodies to dual inhibitors developments in cancer treatment. Bioorg Chem 2024; 151:107695. [PMID: 39137598 DOI: 10.1016/j.bioorg.2024.107695] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Revised: 07/28/2024] [Accepted: 08/04/2024] [Indexed: 08/15/2024]
Abstract
HER2 receptors, overexpressed in certain human cancers, have drawn significant attention in cancer research due to their correlation with poor survival rates. Researchers have developed monoclonal antibodies like Trastuzumab and Pertuzumab against HER2 receptors, which have proven highly beneficial in cancer therapy. Bispecific antibodies like Zanidatamab and antibody-drug conjugates like T-DM1 have been developed to overcome the resistance associated with monotherapy. Small molecules such as Lapatinib, Neratinib, and Pyrotinib were initially developed for treating breast cancer. However, ongoing research is investigating their potential use in other types of cancer, often in combination with other medications. EGFR/HER2 dual-targeted drugs have overcome drug resistance associated with HER2-targeted monotherapy. This comprehensive review covers the structural characteristics of HER2, the HER family signaling pathway mechanism, recent findings regarding HER2 receptor involvement in various cancers, and diverse HER2-targeted therapies. This information provides a comprehensive understanding of HER2-targeted strategies in the evolving field of cancer treatment.
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Affiliation(s)
- Meduri Bhagyalalitha
- Computer Aided Drug Design Laboratory, Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Sri Shivarathreeshwara Nagara, Mysuru 570015 India
| | - Akshatha Handattu Shankaranarayana
- Computer Aided Drug Design Laboratory, Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Sri Shivarathreeshwara Nagara, Mysuru 570015 India
| | - Sethu Arun Kumar
- Computer Aided Drug Design Laboratory, Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Sri Shivarathreeshwara Nagara, Mysuru 570015 India
| | - Manisha Singh
- Computer Aided Drug Design Laboratory, Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Sri Shivarathreeshwara Nagara, Mysuru 570015 India
| | - Karthik G Pujar
- Computer Aided Drug Design Laboratory, Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Sri Shivarathreeshwara Nagara, Mysuru 570015 India
| | - Durgesh Bidye
- Computer Aided Drug Design Laboratory, Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Sri Shivarathreeshwara Nagara, Mysuru 570015 India
| | - Gurubasavaraj Veeranna Pujar
- Computer Aided Drug Design Laboratory, Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Sri Shivarathreeshwara Nagara, Mysuru 570015 India.
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Elshazly AM, Xu J, Melhem N, Abdulnaby A, Elzahed AA, Saleh T, Gewirtz DA. Is Autophagy Targeting a Valid Adjuvant Strategy in Conjunction with Tyrosine Kinase Inhibitors? Cancers (Basel) 2024; 16:2989. [PMID: 39272847 PMCID: PMC11394573 DOI: 10.3390/cancers16172989] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 08/21/2024] [Accepted: 08/23/2024] [Indexed: 09/15/2024] Open
Abstract
Tyrosine kinase inhibitors (TKIs) represent a relatively large class of small-molecule inhibitors that compete with ATP for the catalytic binding site of tyrosine kinase proteins. While TKIs have demonstrated effectiveness in the treatment of multiple malignancies, including chronic myelogenous leukemia, gastrointestinal tumors, non-small cell lung cancers, and HER2-overexpressing breast cancers, as is almost always the case with anti-neoplastic agents, the development of resistance often imposes a limit on drug efficacy. One common survival response utilized by tumor cells to ensure their survival in response to different stressors, including anti-neoplastic drugs, is that of autophagy. The autophagic machinery in response to TKIs in multiple tumor models has largely been shown to be cytoprotective in nature, although there are a number of cases where autophagy has demonstrated a cytotoxic function. In this review, we provide an overview of the literature examining the role that autophagy plays in response to TKIs in different preclinical tumor model systems in an effort to determine whether autophagy suppression or modulation could be an effective adjuvant strategy to increase efficiency and/or overcome resistance to TKIs.
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Affiliation(s)
- Ahmed M. Elshazly
- Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, 401 College St., Richmond, VA 23298, USA;
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt;
| | - Jingwen Xu
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China;
| | - Nebras Melhem
- Department of Anatomy, Physiology and Biochemistry, Faculty of Medicine, The Hashemite University, Zarqa 13133, Jordan;
| | - Alsayed Abdulnaby
- Department of Pharmacognosy, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt;
| | - Aya A. Elzahed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh 33516, Egypt;
| | - Tareq Saleh
- Department of Pharmacology and Public Health, Faculty of Medicine, Hashemite University, Zarqa 13133, Jordan;
| | - David A. Gewirtz
- Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, 401 College St., Richmond, VA 23298, USA;
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Boldig C, Boldig K, Mokhtari S, Etame AB. A Review of the Molecular Determinants of Therapeutic Response in Non-Small Cell Lung Cancer Brain Metastases. Int J Mol Sci 2024; 25:6961. [PMID: 39000069 PMCID: PMC11241836 DOI: 10.3390/ijms25136961] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 06/20/2024] [Accepted: 06/21/2024] [Indexed: 07/16/2024] Open
Abstract
Lung cancer is a leading cause of cancer-related morbidity and mortality worldwide. Metastases in the brain are a common hallmark of advanced stages of the disease, contributing to a dismal prognosis. Lung cancer can be broadly classified as either small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC). NSCLC represents the most predominant histology subtype of lung cancer, accounting for the majority of lung cancer cases. Recent advances in molecular genetics, coupled with innovations in small molecule drug discovery strategies, have facilitated both the molecular classification and precision targeting of NSCLC based on oncogenic driver mutations. Furthermore, these precision-based strategies have demonstrable efficacy across the blood-brain barrier, leading to positive outcomes in patients with brain metastases. This review provides an overview of the clinical features of lung cancer brain metastases, as well as the molecular mechanisms that drive NSCLC oncogenesis. We also explore how precision medicine-based strategies can be leveraged to improve NSCLC brain metastases.
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Affiliation(s)
- Catherine Boldig
- Department of Neurology, University of South Florida, 2 Tampa General Circle, Tampa, FL 33606, USA
| | - Kimberly Boldig
- Department of Internal Medicine, University of Florida Jacksonville, 655 W. 8th St., Jacksonville, FL 32209, USA
| | - Sepideh Mokhtari
- Moffitt Cancer Center, Department of Neuro-Oncology, 12902 USF Magnolia Drive, Tampa, FL 33612, USA
| | - Arnold B Etame
- Moffitt Cancer Center, Department of Neuro-Oncology, 12902 USF Magnolia Drive, Tampa, FL 33612, USA
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Hu ZY, Wang WJ, Hu L, Shi JH, Jiang SL. Comprehending the intermolecular interaction of dacomitinib with bovine serum albumin: experimental and theoretical approaches. J Biomol Struct Dyn 2024; 42:3579-3592. [PMID: 37288787 DOI: 10.1080/07391102.2023.2218926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Accepted: 05/08/2023] [Indexed: 06/09/2023]
Abstract
Dacomitinib (DAC), as a member of tyrosine kinase inhibitors is primarily used to treat non-small cell lung cancer. The intermolecular interaction between DAC and bovine serum albumin (BSA) was comprehended with the help of experiments and theoretical simulations. The outcomes indicated that DAC quenched the endogenous fluorescence of BSA through static quenching mode. In the binding process, DAC was preferentially inserted into the hydrophobic cavity of BSA subdomain IA (site III), and a fluorescence-free DAC-BSA complex with molar ratio of 1:1 was generated. The outcomes confirmed that DAC had a stronger affinity on BSA and the non-radiative energy transfer occurred in the combination process of two. And, it can be inferred from the outcomes of thermodynamic parameters and competition experiments with 8-aniline-1-naphthalenesulfonic acid (ANS) and D-(+)- sucrose that hydrogen bonds (H-bonds), van der Waals forces (vdW) and hydrophobic forces had a significant impact in inserting DAC into the hydrophobic cavity of BSA. The outcomes from multi-spectroscopic measurements that DAC could affect the secondary structure of BSA, that was, α-helix content decreased slightly from 51.0% to 49.7%. Moreover, the combination of DAC and BSA led to a reduction in the hydrophobicity of the microenvironment around tyrosine (Tyr) residues in BSA while had little influence on the microenvironment of around tryptophan (Trp) residues. The outcomes from molecular docking and molecular dynamics (MD) simulation further demonstrated the insertion of DAC into site III of BSA and hydrogen energy and van der Waals energy were the dominant energy of DAC-BSA stability. In addition, the influence of metal ions (Fe3+, Cu2+, Co2+, etc.) on the affinity of the system was explored.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Zhe-Ying Hu
- College of Pharmaceutic Science, Zhejiang University of Technology, Hangzhou, China
| | - Wan-Jun Wang
- College of Pharmaceutic Science, Zhejiang University of Technology, Hangzhou, China
| | - Lu Hu
- College of Pharmaceutic Science, Zhejiang University of Technology, Hangzhou, China
| | - Jie-Hua Shi
- College of Pharmaceutic Science, Zhejiang University of Technology, Hangzhou, China
| | - Shao-Liang Jiang
- College of Pharmaceutic Science, Zhejiang University of Technology, Hangzhou, China
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Liu J, Lin S, Huynh A, Tan W. Effects of H2-Receptor Antagonists on the Exposure of Dacomitinib. Pharmaceutics 2024; 16:118. [PMID: 38258127 PMCID: PMC10819565 DOI: 10.3390/pharmaceutics16010118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 01/05/2024] [Accepted: 01/11/2024] [Indexed: 01/24/2024] Open
Abstract
Dacomitinib is an irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor indicated for the treatment of patients with advanced non-small-cell lung cancer (NSCLC) and EGFR-activating mutations. Proton-pump inhibitors decreased dacomitinib exposure. This analysis summarizes the effect of Histamine-2 receptor antagonists (H2RAs) on dacomitinib exposure. A within-patient comparison of the steady-state trough concentrations (Ctrough,ss) of dacomitinib and its active metabolite and active moiety with and without concomitant use of H2RAs was conducted using a linear mixed effects model with pooled data from 11 clinical studies in patients with NSCLC. An oral absorption physiologically based pharmacokinetic (PBPK) model was constructed and verified using clinical pharmacokinetic (PK) data after a single dose of dacomitinib in healthy volunteers to estimate the effect of gastric pH altered by an H2RA on dacomitinib's PKs. The adjusted geometric mean of the dacomitinib Ctrough,ss of the dacomitinib parent, metabolite and active moiety following co-administration with an H2RA was approximately 86%, 104% and 100% relative to that following dacomitinib 45 mg administration without an H2RA (p > 0.05). The PBPK modeling showed negligible change in dacomitinib maximum concentration (Cmax) and area under the drug concentration-time curve (AUC) over 0-24 h after H2RA administration when compared with those administered dacomitinib alone. Co-administration of an H2RA with dacomitinib is not expected to have any clinically relevant effect on dacomitinib exposure.
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Affiliation(s)
- Jian Liu
- Clinical Pharmacology, Pfizer Investment Co., Ltd., Beijing 100010, China;
| | - Swan Lin
- Clinical Pharmacology, Global Product Development, Pfizer Inc., San Diego, CA 92121, USA;
| | - Anthony Huynh
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, CA 92093, USA
| | - Weiwei Tan
- Clinical Pharmacology, Global Product Development, Pfizer Inc., San Diego, CA 92121, USA;
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Rae S, Plummer E, Fitzgerald L, Hogarth L, Bridgewood A, Brown-Schofield L, Graham J, Haigh S, McAnulty C, Drew Y, Haris N, Bashir S, Plummer R, Greystoke A. Prevalence of mutations in common tumour types in Northern England and comparable utility of national and international Trial Finders. J Cancer Res Clin Oncol 2023; 149:16355-16363. [PMID: 37702806 PMCID: PMC10645649 DOI: 10.1007/s00432-023-05365-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Accepted: 08/28/2023] [Indexed: 09/14/2023]
Abstract
PURPOSE Tumour genomic profiling is of increasing importance in early phase trials to match patients to targeted therapeutics. Mutations vary by demographic group; however, regional differences are not characterised. This was investigated by comparing mutation prevalence for common cancers presenting to Newcastle Experimental Cancer Medicine Centre (ECMC) to The Cancer Genome Atlas (TCGA) and utility of trial matching modalities. METHODS Detailed clinicogenomic data were obtained for patients presenting September 2017-December 2020. Prevalence of mutations in lung, colorectal, breast and prostate cancer was compared to TCGA GDC Data Portal. Experimental Cancer (EC) Trial Finder utility in matching trials was compared to a Molecular Tumour Board (MTB) and commercial sequencing reports. RESULTS Of 311 patients with advanced cancer, this consisted of lung (n = 131, 42.1%), colorectal (n = 44, 14.1%), breast (n = 36, 11.6%) and prostate (n = 18, 5.6%). More than one mutation was identified in the majority (n = 260, 84%). Significant prevalence differences compared to TCGA were identified, including a high prevalence of EGFR in lung (P = 0.001); RB1 in breast (P = 0.0002); and multiple mutations in prostate cancer. EC Trial Finder demonstrated significantly different utility than sequencing reports in identifying trials (P = 0.007). CONCLUSIONS Regional differences in mutations may exist with advanced stage accounting for prevalence of specific mutations. A national Trial Finder shows utility in finding targeted trials whilst commercial sequencing reports may over-report 'actionable' mutations. Understanding local prevalence and trial availability could increase enrolment onto matched early phase trials.
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Affiliation(s)
- S Rae
- Sir Bobby Robson Cancer Trials Research Centre, Northern Centre for Cancer Care, Freeman Hospital, Freeman Road, Newcastle upon Tyne, NE7 7DN, UK.
- Newcastle University, Newcastle upon Tyne, NE1 7RU, UK.
| | - E Plummer
- Sir Bobby Robson Cancer Trials Research Centre, Northern Centre for Cancer Care, Freeman Hospital, Freeman Road, Newcastle upon Tyne, NE7 7DN, UK
| | - L Fitzgerald
- Sir Bobby Robson Cancer Trials Research Centre, Northern Centre for Cancer Care, Freeman Hospital, Freeman Road, Newcastle upon Tyne, NE7 7DN, UK
- Newcastle University, Newcastle upon Tyne, NE1 7RU, UK
| | - L Hogarth
- Sir Bobby Robson Cancer Trials Research Centre, Northern Centre for Cancer Care, Freeman Hospital, Freeman Road, Newcastle upon Tyne, NE7 7DN, UK
- Newcastle University, Newcastle upon Tyne, NE1 7RU, UK
| | - A Bridgewood
- Sir Bobby Robson Cancer Trials Research Centre, Northern Centre for Cancer Care, Freeman Hospital, Freeman Road, Newcastle upon Tyne, NE7 7DN, UK
| | - L Brown-Schofield
- Sir Bobby Robson Cancer Trials Research Centre, Northern Centre for Cancer Care, Freeman Hospital, Freeman Road, Newcastle upon Tyne, NE7 7DN, UK
| | - J Graham
- Sir Bobby Robson Cancer Trials Research Centre, Northern Centre for Cancer Care, Freeman Hospital, Freeman Road, Newcastle upon Tyne, NE7 7DN, UK
| | - S Haigh
- Sir Bobby Robson Cancer Trials Research Centre, Northern Centre for Cancer Care, Freeman Hospital, Freeman Road, Newcastle upon Tyne, NE7 7DN, UK
| | - C McAnulty
- Newcastle Genetics Laboratory, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, NE7 7DN, UK
| | - Y Drew
- BC Cancer Centre, Vancouver, 600W 10th Avenue, Vancouver, BC, V5Z 4E6, Canada
- University of British Columbia, Vancouver, BC, V6T 1Z4, Canada
| | - N Haris
- Sir Bobby Robson Cancer Trials Research Centre, Northern Centre for Cancer Care, Freeman Hospital, Freeman Road, Newcastle upon Tyne, NE7 7DN, UK
- Newcastle University, Newcastle upon Tyne, NE1 7RU, UK
| | - S Bashir
- Sir Bobby Robson Cancer Trials Research Centre, Northern Centre for Cancer Care, Freeman Hospital, Freeman Road, Newcastle upon Tyne, NE7 7DN, UK
| | - R Plummer
- Sir Bobby Robson Cancer Trials Research Centre, Northern Centre for Cancer Care, Freeman Hospital, Freeman Road, Newcastle upon Tyne, NE7 7DN, UK
- Newcastle University, Newcastle upon Tyne, NE1 7RU, UK
| | - A Greystoke
- Sir Bobby Robson Cancer Trials Research Centre, Northern Centre for Cancer Care, Freeman Hospital, Freeman Road, Newcastle upon Tyne, NE7 7DN, UK
- Newcastle University, Newcastle upon Tyne, NE1 7RU, UK
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Ohnmacht AJ, Rajamani A, Avar G, Kutkaite G, Gonçalves E, Saur D, Menden MP. The pharmacoepigenomic landscape of cancer cell lines reveals the epigenetic component of drug sensitivity. Commun Biol 2023; 6:825. [PMID: 37558831 PMCID: PMC10412573 DOI: 10.1038/s42003-023-05198-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Accepted: 08/01/2023] [Indexed: 08/11/2023] Open
Abstract
Aberrant DNA methylation accompanies genetic alterations during oncogenesis and tumour homeostasis and contributes to the transcriptional deregulation of key signalling pathways in cancer. Despite increasing efforts in DNA methylation profiling of cancer patients, there is still a lack of epigenetic biomarkers to predict treatment efficacy. To address this, we analyse 721 cancer cell lines across 22 cancer types treated with 453 anti-cancer compounds. We systematically detect the predictive component of DNA methylation in the context of transcriptional and mutational patterns, i.e., in total 19 DNA methylation biomarkers across 17 drugs and five cancer types. DNA methylation constitutes drug sensitivity biomarkers by mediating the expression of proximal genes, thereby enhancing biological signals across multi-omics data modalities. Our method reproduces anticipated associations, and in addition, we find that the NEK9 promoter hypermethylation may confer sensitivity to the NEDD8-activating enzyme (NAE) inhibitor pevonedistat in melanoma through downregulation of NEK9. In summary, we envision that epigenomics will refine existing patient stratification, thus empowering the next generation of precision oncology.
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Affiliation(s)
- Alexander Joschua Ohnmacht
- Computational Health Center, Helmholtz Munich, 85764, Neuherberg, Germany
- Department of Biology, Ludwig-Maximilians University Munich, 82152, Martinsried, Germany
| | - Anantharamanan Rajamani
- Division of Translational Cancer Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
- Chair of Translational Cancer Research and Institute of Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany
- Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Ismaninger Str. 22, 81675, Munich, Germany
| | - Göksu Avar
- Computational Health Center, Helmholtz Munich, 85764, Neuherberg, Germany
- Department of Biology, Ludwig-Maximilians University Munich, 82152, Martinsried, Germany
| | - Ginte Kutkaite
- Computational Health Center, Helmholtz Munich, 85764, Neuherberg, Germany
- Department of Biology, Ludwig-Maximilians University Munich, 82152, Martinsried, Germany
| | - Emanuel Gonçalves
- Instituto Superior Técnico (IST), Universidade de Lisboa, 1049-001, Lisbon, Portugal
- INESC-ID, 1000-029, Lisbon, Portugal
| | - Dieter Saur
- Division of Translational Cancer Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany
- Chair of Translational Cancer Research and Institute of Experimental Cancer Therapy, Klinikum rechts der Isar, School of Medicine, Technische Universität München, Ismaninger Str. 22, 81675, Munich, Germany
- Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Ismaninger Str. 22, 81675, Munich, Germany
| | - Michael Patrick Menden
- Computational Health Center, Helmholtz Munich, 85764, Neuherberg, Germany.
- Department of Biology, Ludwig-Maximilians University Munich, 82152, Martinsried, Germany.
- Department of Biochemistry and Pharmacology, University of Melbourne, Victoria, VIC, 3010, Australia.
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Alali M, Saifo M. Optimizing the Treatment for Advanced Non-Small-Cell Lung Cancer with Mutated Epidermal Growth Factor Receptor in Low-Income Countries: A Review. JOURNAL OF IMMUNOTHERAPY AND PRECISION ONCOLOGY 2023; 6:140-149. [PMID: 37637235 PMCID: PMC10448734 DOI: 10.36401/jipo-22-29] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 02/27/2023] [Accepted: 03/03/2023] [Indexed: 08/29/2023]
Abstract
Introduction Osimertinib is the treatment of choice for epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC). Because of its high price, many low-income countries, such as Syria, cannot provide osimertinib, which makes it difficult to choose the appropriate treatment for these patients. This study aimed to review articles that assessed tyrosine kinase inhibitors (TKIs) for advanced NSCLC and developed an appropriate treatment plan for Syrian patients. Methods An electronic literature search was conducted of published phase II and III studies that assessed the efficacy of EGFR-TKIs for advanced NSCLC between January 2003 and May 2022. Results Seventeen articles were reviewed. The results were similar when erlotinib or icotinib was compared with gefitinib. Progression-free survival and overall survival for afatinib and dacomitinib were longer than for gefitinib, with small significant differences. Osimertinib was the only TKI that showed efficacy against the T790M mutation, which showed an improvement over the first- and second-generation TKIs. Osimertinib as a first-line therapy is not cost-effective compared with first- and second-generation TKIs. Conclusion Osimertinib is the preferred first-line treatment in patients with advanced EGFR-mutated NSCLC. First- and second-generation TKIs are still considered good options, especially in low-income countries that cannot cover the costs of osimertinib.
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Affiliation(s)
- Mousa Alali
- Department of Oncology, Albairouni University Hospital, Faculty of Medicine, Damascus University, Damascus, Syrian Arab Republic
| | - Maher Saifo
- Department of Oncology, Albairouni University Hospital, Faculty of Medicine, Damascus University, Damascus, Syrian Arab Republic
- Faculty of Pharmacy, Alsham Private University, Damascus, Syrian Arab Republic
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10
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Liu X, Guo Q, Gao G, Cao Z, Guan Z, Jia B, Wang W, Zhang K, Zhang W, Wang S, Li W, Hao Q, Zhang Y, Li M, Zhang W, Gu J. Exosome-transmitted circCABIN1 promotes temozolomide resistance in glioblastoma via sustaining ErbB downstream signaling. J Nanobiotechnology 2023; 21:45. [PMID: 36755314 PMCID: PMC9906870 DOI: 10.1186/s12951-023-01801-w] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 01/31/2023] [Indexed: 02/10/2023] Open
Abstract
Although temozolomide (TMZ) provides significant clinical benefit for glioblastoma (GBM), responses are limited by the emergence of acquired resistance. Here, we demonstrate that exosomal circCABIN1 secreted from TMZ-resistant cells was packaged into exosomes and then disseminated TMZ resistance of receipt cells. CircCABIN1 could be cyclized by eukaryotic translation initiation factor 4A3 (EIF4A3) and is highly expressed in GBM tissues and glioma stem cells (GSCs). CircCABIN1 is required for the self-renewal maintenance of GSCs to initiate acquired resistance. Mechanistically, circCABIN1 regulated the expression of olfactomedin-like 3 (OLFML3) by sponging miR-637. Moreover, upregulation of OLFML3 activating the ErbB signaling pathway and ultimately contributing to stemness reprogramming and TMZ resistance. Treatment of GBM orthotopic mice xenografts with engineered exosomes targeting circCABIN1 and OLFML3 provided prominent targetability and had significantly improved antitumor activity of TMZ. In summary, our work proposed a novel mechanism for drug resistance transmission in GBM and provided evidence that engineered exosomes are a promising clinical tool for cancer prevention and therapy.
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Affiliation(s)
- Xiao Liu
- State Key Laboratory of Cancer Biology, School of Pharmacy, Biotechnology Center, The Fourth Military Medical University, Xi’an, China
- Department of Hematology, Xijing Hospital, Xi’an, China
| | - Qingdong Guo
- Department of Neurosurgery, Xijing Hospital, Xi’an, China
| | - Guangxun Gao
- Department of Hematology, Xijing Hospital, Xi’an, China
| | - Zhengcong Cao
- State Key Laboratory of Cancer Biology, School of Pharmacy, Biotechnology Center, The Fourth Military Medical University, Xi’an, China
| | - Zhihao Guan
- State Key Laboratory of Cancer Biology, School of Pharmacy, Biotechnology Center, The Fourth Military Medical University, Xi’an, China
| | - Bo Jia
- Department of Neurosurgery, Xijing Hospital, Xi’an, China
| | - Weizhong Wang
- Department of Neurosurgery, Xijing Hospital, Xi’an, China
| | - Kuo Zhang
- State Key Laboratory of Cancer Biology, School of Pharmacy, Biotechnology Center, The Fourth Military Medical University, Xi’an, China
| | - Wangqian Zhang
- State Key Laboratory of Cancer Biology, School of Pharmacy, Biotechnology Center, The Fourth Military Medical University, Xi’an, China
| | - Shuning Wang
- State Key Laboratory of Cancer Biology, School of Pharmacy, Biotechnology Center, The Fourth Military Medical University, Xi’an, China
| | - Weina Li
- State Key Laboratory of Cancer Biology, School of Pharmacy, Biotechnology Center, The Fourth Military Medical University, Xi’an, China
| | - Qiang Hao
- State Key Laboratory of Cancer Biology, School of Pharmacy, Biotechnology Center, The Fourth Military Medical University, Xi’an, China
| | - Yingqi Zhang
- State Key Laboratory of Cancer Biology, School of Pharmacy, Biotechnology Center, The Fourth Military Medical University, Xi’an, China
| | - Meng Li
- State Key Laboratory of Cancer Biology, School of Pharmacy, Biotechnology Center, The Fourth Military Medical University, Xi’an, China
| | - Wei Zhang
- State Key Laboratory of Cancer Biology, School of Pharmacy, Biotechnology Center, The Fourth Military Medical University, Xi’an, China
| | - Jintao Gu
- State Key Laboratory of Cancer Biology, School of Pharmacy, Biotechnology Center, The Fourth Military Medical University, Xi’an, China
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11
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Identification of MYEOV-Associated Gene Network as a Potential Therapeutic Target in Pancreatic Cancer. Cancers (Basel) 2022; 14:cancers14215439. [DOI: 10.3390/cancers14215439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Accepted: 11/02/2022] [Indexed: 11/09/2022] Open
Abstract
The molecular mechanism that promotes pancreatic cancer remains unclear, so it is important to find the molecular network of important genes related to pancreatic cancer. To find the key molecule of pancreatic cancer, differential gene expression analyses were analyzed by the Deseq2 package, edgeR package, and limma-voom package, respectively. Pancreatic cancer survival-related genes were analyzed by COX survival analysis. Finally, we integrated the results to obtain the significantly differentially expressed gene, MYEOV (myeloma overexpressed gene), most strongly related to survival in pancreatic cancer. Experimental verification by qRT-PCR confirmed that transcription levels of MYEOV mRNA markedly increased in pancreatic cancer cells relative to normal human pancreatic ductal epithelial cells (HPDE). Through the comprehensive analysis of multiple databases, we constructed a molecular network centered on MYEOV and found specific links between molecules in this network and tumor-associated immune cells. It was noted that MYEOV could serve as a ceRNA by producing molecular sponging effects on hsa-miR-103a-3p and hsa-miR-107, thus affecting the role of GPRC5A, SERPINB5, EGFR, KRAS, EIF4G2, and PDCD4 on pancreatic cancer progression. Besides, we also identified that infiltrated immune cells are potential mediators for the molecules in the MYEOV-related network to promote pancreatic cancer progression. It is the first report to focus on the possibility that MYEOV may act as a competing endogenous RNA (ceRNA) to form an interactive network with some pancreatic cancer-related genes such as KRAS and serve as a key therapeutic target of pancreatic cancer treatment.
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12
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Hintzen G, Dulat HJ, Rajkovic E. Engaging innate immunity for targeting the epidermal growth factor receptor: Therapeutic options leveraging innate immunity versus adaptive immunity versus inhibition of signaling. Front Oncol 2022; 12:892212. [PMID: 36185288 PMCID: PMC9518002 DOI: 10.3389/fonc.2022.892212] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 07/28/2022] [Indexed: 12/15/2022] Open
Abstract
The epidermal growth factor receptor (EGFR) is a key player in the normal tissue physiology and the pathology of cancer. Therapeutic approaches have now been developed to target oncogenic genetic aberrations of EGFR, found in a subset of tumors, and to take advantage of overexpression of EGFR in tumors. The development of small-molecule inhibitors and anti-EGFR antibodies targeting EGFR activation have resulted in effective but limited treatment options for patients with mutated or wild-type EGFR-expressing cancers, while therapeutic approaches that deploy effectors of the adaptive or innate immune system are still undergoing development. This review discusses EGFR-targeting therapies acting through distinct molecular mechanisms to destroy EGFR-expressing cancer cells. The focus is on the successes and limitations of therapies targeting the activation of EGFR versus those that exploit the cytotoxic T cells and innate immune cells to target EGFR-expressing cancer cells. Moreover, we discuss alternative approaches that may have the potential to overcome limitations of current therapies; in particular the innate cell engagers are discussed. Furthermore, this review highlights the potential to combine innate cell engagers with immunotherapies, to maximize their effectiveness, or with unspecific cell therapies, to convert them into tumor-specific agents.
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13
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Qiao F, Chen Q, Lu W, Fang N. Plasma exchange treats severe intrahepatic cholestasis caused by dacomitinib: A case report. Medicine (Baltimore) 2022; 101:e29629. [PMID: 35801736 PMCID: PMC9259143 DOI: 10.1097/md.0000000000029629] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
RATIONALE Dacomitinib-induced liver injury is often manifested by mild elevations of transaminases and bilirubin, and severe intrahepatic cholestasis caused by dacomitinib for simultaneous taking orally cytochrome P450 2D6 (CYP2D6) competitive substrates has been rarely reported. PATIENT CONCERNS The patient was a 69-year-old woman with non-small cell lung cancer (NSCLC) who was prescribed oral dacomitinib for a month; she was given oral loratadine due to "allergic rhinitis" and metoprolol extended action tablets due to "tachycardia" separately for a few days during the course of dacomitinib treatment. The patient developed liver damage, increased fatigue, yellow urine, and pruritus, with significantly elevated serum levels of bilirubin and glutamyltranspetidase. DIAGNOSIS Intrahepatic cholestasis, drug-induced liver injury, and NSCLC. INTERVENTIONS After admission, the patient was prescribed adenosylmethionine, acetylcysteine, ursodeoxycholic acid capsule, methylprednisolone and fenofibrate for a month, with progressive elevation of liver biochemical parameters. Through drug enzyme gene assays in the liver tissue after percutaneous liver biopsy, we found both CYP2D6*10/*10 and ATP-binding cassette subfamily B member 1 GG variants (rs1045642) positive. After the poor response to the conventional medication, the patient underwent plasma exchange. OUTCOMES The patient was discharged after her liver parameters improved; the parameters remained normal at several follow-up visits, and she renewed the NSCLC regimens without dacomitinib after being evaluated by oncologists. LESSONS Dacomitinib can induce severe intrahepatic cholestasis. It is considered that patients with intermediate metabolic CYP2D6 are susceptible to drug-induced liver injury caused by dacomitinib; plasma exchange may be an effective treatment.
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Affiliation(s)
- Fei Qiao
- Department of Hepatology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China
| | - Qinlei Chen
- Department of Hepatology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China
| | - Weiting Lu
- Department of Hepatology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China
| | - Nanyuan Fang
- Department of Hepatology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, China
- *Correspondence: Nanyuan Fang, Department of Hepatology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, No. 155, Hanzhong Rd, Nanjing, China (e-mail: )
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14
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K SK, Choppala AD. Development and Optimization of Osimertinib-loaded Biodegradable Polymeric Nanoparticles Enhance In-vitro Cytotoxicity in Mutant EGFR NSCLC Cell Models and In-vivo Tumor Reduction in H1975 Xenograft Mice Models. AAPS PharmSciTech 2022; 23:159. [PMID: 35676448 DOI: 10.1208/s12249-022-02314-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Accepted: 05/19/2022] [Indexed: 11/30/2022] Open
Abstract
Osimertinib (OMB), a third-generation EGFR inhibitor, specifically and irreversibly inhibits EGFRT790M mutant form. Nevertheless, its clinical use is limited due to poor solubility, low absorption, and oral bioavailability. To overcome the low therapeutic capabilities of the free drug, we developed OMB-loaded PCL or CHS nanoparticles and characterized them. Among fifteen devised nanoparticle formulations (Npfs), OMB-PCL-f3, f9, and OMB-CHS-f3 showed great characteristics such as particle size (ranges from 101.3 ± 8.2 to 119.7 ± 10.4 nm), zeta potential (-36.4 ± 3.2 to -31.7 ± 3.9 mV), and polydispersity index (0.227 ± 0.037 to 0.261 ± 0.025). The % entrapment (91.25 ± 5.84 to 95.25 ± 5.88) and drug loading (29.64 ± 2.38 to 33.59 ± 2.36) indicated the formulation optimization. OMB-CHS-f3 demonstrated long-term in-vitro release, with a % cumulative OMB release of 99.99 ± 2.67 within 24 h, and the cytotoxicity of OMB-CHS-f3 showed 2.6- and 2.4-fold superior activity in mutant EGFR harboring H1975 and PC-9 cells, respectively, compared to plain OMB. Quantitative assessment of OMB cellular uptake from OMB-CHS-f3 showed superior drug accumulation of 81.59 ± 5.8% and 77.31 ± 4.6% in H1975 and PC-9 cells which was more than OMB-CHS-f9 and plain OMB. Flow cytometric cell cycle analysis revealed that OMB-CHS-f3 triggered G2/M phase arrest greater than OMB-PCL-f9 and plain OMB. In vivo, OMB-CHS-f3 Npf treatment reduced tumor size and body weight gain compared to Tagrisso treatment (p < 0.05). These findings showed that chitosan-coated OMB Npfs might improve outcomes by overcoming complications, including resistance and disease recurrence in NSCLC patients.
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Affiliation(s)
- Sanjay Kumar K
- GITAM Institute of Pharmacy, GITAM (Deemed to be University), Visakhapatnam, Andhra Pradesh, 500035, India
| | - Asha Deepti Choppala
- GITAM Institute of Pharmacy, GITAM (Deemed to be University), Visakhapatnam, Andhra Pradesh, 500035, India.
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15
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Abughanimeh O, Kaur A, El Osta B, Ganti AK. Novel targeted therapies for advanced non-small lung cancer. Semin Oncol 2022; 49:326-336. [PMID: 35414419 DOI: 10.1053/j.seminoncol.2022.03.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 12/05/2021] [Accepted: 03/12/2022] [Indexed: 11/11/2022]
Abstract
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer accounting for almost 80%-85% of all lung cancer cases. Unfortunately, more than half of the patients will be diagnosed with advanced disease at the time of presentation, which makes their disease incurable. Historically, the 5 year overall survival for advanced NSCLC was 5%. However, there has been a significant increase in our understanding of the genetic basis of NSCLC, which has led to development of both immunotherapy and targeted therapy agents. This has improved the 5 year overall survival to become within the range of 15%-50% depending on certain mutations and biomarkers. Over the last decade the United States Food and Drug Administration (FDA) has approved almost 20 new targeted therapies and clinical trials are still undergoing to evaluate more novel agents. In this review, we will present recent updates on novel targeted therapies.
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Affiliation(s)
- Omar Abughanimeh
- Division of Oncology and Hematology, Department of Internal Medicine, University of Nebraska Medical Center- Fred and Pamela Buffett Cancer Center, Omaha, NE
| | - Anahat Kaur
- Albert Einstein College of Medicine/Jacobi Medical Center, Bronx, NY
| | - Badi El Osta
- Department of Hematology and Oncology, Atlanta VA Health Care System, Decatur, GA; Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA
| | - Apar Kishor Ganti
- Division of Oncology and Hematology, Department of Internal Medicine, University of Nebraska Medical Center- Fred and Pamela Buffett Cancer Center, Omaha, NE; Division of Oncology and Hematology, VA Nebraska-Western Iowa Health Care System, Omaha, NE.
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16
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Rui M, Wang Z, Fei Z, Wu Y, Wang Y, Sun L, Shang Y, Li H. The Relationship Between Short-Term Surrogate Endpoint Indicators and mPFS and mOS in Clinical Trials of Malignant Tumors: A Case Study of Approved Molecular Targeted Drugs for Non-Small-Cell Lung Cancer in China. Front Pharmacol 2022; 13:862640. [PMID: 35370659 PMCID: PMC8966682 DOI: 10.3389/fphar.2022.862640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 02/28/2022] [Indexed: 11/13/2022] Open
Abstract
Objective: Due to the initiation of the priority review program in China, many antitumor drugs have been approved for marketing based on phase II clinical trials and short-term surrogate endpoint indicators. This study used approved targeted drugs for the treatment of non-small-cell lung cancer (NSCLC) in China as an example to evaluate the association between short-term surrogate endpoints [objective response rate (ORR) and disease control rate (DCR)] and median progression-free survival (mPFS) and median overall survival (mOS). Methods: Five databases, i.e., MEDLINE, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), and Wanfang Data were searched, for phase II or phase III clinical trials of all molecular targeted drugs that have been marketed in China for the treatment of NSCLC. After screening the literature and extracting information, both univariate and multivariate linear regression were performed on the short-term surrogate indicators and mPFS and mOS to explore the relationship. Results: A total of 63 studies were included (25 studies with only ORR, DCR, and mPFS and 39 studies with ORR, DCR, mPFS, and mOS). In terms of the targeted drugs for the treatment of NSCLC, in addition to the good but not excellent linear relationship between DCR and mOS (0.4 < R2 adj = 0.5653 < 0.6), all other short-term surrogate endpoint indicators had excellent linear relationships with mPFS and mOS (R2 adj≥0.6), while mPFS and mOS had the most excellent linear relationships (R2 adj = 0.8036). Conclusion: For targeted drugs for the treatment of NSCLC, short-term surrogate endpoint indicators such as ORR and DCR may be reliable surrogate indicators for mPFS and mOS. However, whether short-term surrogate endpoint indicators can be used to predict final endpoints remains to be verified.
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Affiliation(s)
- Mingjun Rui
- School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing, China
- Center for Pharmacoeconomics and Outcomes Research, China Pharmaceutical University, Nanjing, China
| | - Zijing Wang
- School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing, China
- Center for Pharmacoeconomics and Outcomes Research, China Pharmaceutical University, Nanjing, China
| | - Zhengyang Fei
- School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing, China
- Center for Pharmacoeconomics and Outcomes Research, China Pharmaceutical University, Nanjing, China
| | - Yao Wu
- School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing, China
- Center for Pharmacoeconomics and Outcomes Research, China Pharmaceutical University, Nanjing, China
| | - Yingcheng Wang
- School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing, China
- Center for Pharmacoeconomics and Outcomes Research, China Pharmaceutical University, Nanjing, China
| | - Lei Sun
- School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing, China
| | - Ye Shang
- School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing, China
- Center for Pharmacoeconomics and Outcomes Research, China Pharmaceutical University, Nanjing, China
| | - Hongchao Li
- School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing, China
- Center for Pharmacoeconomics and Outcomes Research, China Pharmaceutical University, Nanjing, China
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17
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Papini F, Sundaresan J, Leonetti A, Tiseo M, Rolfo C, Peters GJ, Giovannetti E. Hype or hope - Can combination therapies with third-generation EGFR-TKIs help overcome acquired resistance and improve outcomes in EGFR-mutant advanced/metastatic NSCLC? Crit Rev Oncol Hematol 2021; 166:103454. [PMID: 34455092 DOI: 10.1016/j.critrevonc.2021.103454] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 08/07/2021] [Accepted: 08/10/2021] [Indexed: 02/08/2023] Open
Abstract
Three generations of epidermal growth factor receptor - tyrosine kinase inhibitors (EGFR-TKIs) have been developed for treating advanced/metastatic non-small cell lung cancer (NSCLC) patients harboring EGFR-activating mutations, while a fourth generation is undergoing preclinical assessment. Although initially effective, acquired resistance to EGFR-TKIs usually arises within a year due to the emergence of clones harboring multiple resistance mechanisms. Therefore, the combination of EGFR-TKIs with other therapeutic agents has emerged as a potential strategy to overcome resistance and improve clinical outcomes. However, results obtained so far are ambiguous and ideal therapies for patients who experience disease progression during treatment with EGFR-TKIs remain elusive. This review provides an updated landscape of EGFR-TKIs, along with a description of the mechanisms causing resistance to these drugs. Moreover, it discusses the current knowledge, limitations, and future perspective regarding the use of EGFR-TKIs in combination with other anticancer agents, supporting the need for bench-to-bedside approaches in selected populations.
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Affiliation(s)
- Filippo Papini
- Department of Medical Oncology, Amsterdam UMC, VU University, Cancer Center Amsterdam, Amsterdam, the Netherlands; Fondazione Pisana per la Scienza, Pisa, Italy
| | - Janani Sundaresan
- Department of Medical Oncology, Amsterdam UMC, VU University, Cancer Center Amsterdam, Amsterdam, the Netherlands
| | - Alessandro Leonetti
- Department of Medical Oncology, Amsterdam UMC, VU University, Cancer Center Amsterdam, Amsterdam, the Netherlands; Department of Medicine and Surgery, University of Parma, Parma, Italy; Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Marcello Tiseo
- Department of Medicine and Surgery, University of Parma, Parma, Italy; Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Christian Rolfo
- The Center of Thoracic Oncology at the Tisch Cancer Institute, Mount Sinai, NYC, United States
| | - Godefridus J Peters
- Department of Medical Oncology, Amsterdam UMC, VU University, Cancer Center Amsterdam, Amsterdam, the Netherlands; Department of Biochemistry, Medical University of Gdansk, Poland
| | - Elisa Giovannetti
- Department of Medical Oncology, Amsterdam UMC, VU University, Cancer Center Amsterdam, Amsterdam, the Netherlands; Fondazione Pisana per la Scienza, Pisa, Italy.
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Reita D, Pabst L, Pencreach E, Guérin E, Dano L, Rimelen V, Voegeli AC, Vallat L, Mascaux C, Beau-Faller M. Molecular Mechanism of EGFR-TKI Resistance in EGFR-Mutated Non-Small Cell Lung Cancer: Application to Biological Diagnostic and Monitoring. Cancers (Basel) 2021; 13:4926. [PMID: 34638411 PMCID: PMC8507869 DOI: 10.3390/cancers13194926] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 09/20/2021] [Accepted: 09/23/2021] [Indexed: 12/21/2022] Open
Abstract
Non-small cell lung cancer (NSCLC) is the most common cancer in the world. Activating epidermal growth factor receptor (EGFR) gene mutations are a positive predictive factor for EGFR tyrosine kinase inhibitors (TKIs). For common EGFR mutations (Del19, L858R), the standard first-line treatment is actually third-generation TKI, osimertinib. In the case of first-line treatment by first (erlotinib, gefitinib)- or second-generation (afatinib) TKIs, osimertinib is approved in second-line treatment for patients with T790M EGFR mutation. Despite the excellent disease control results with EGFR TKIs, acquired resistance inevitably occurs and remains a biological challenge. This leads to the discovery of novel biomarkers and possible drug targets, which vary among the generation/line of EGFR TKIs. Besides EGFR second/third mutations, alternative mechanisms could be involved, such as gene amplification or gene fusion, which could be detected by different molecular techniques on different types of biological samples. Histological transformation is another mechanism of resistance with some biological predictive factors that needs tumor biopsy. The place of liquid biopsy also depends on the generation/line of EGFR TKIs and should be a good candidate for molecular monitoring. This article is based on the literature and proposes actual and future directions in clinical and translational research.
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Affiliation(s)
- Damien Reita
- Department of Biochemistry and Molecular Biology, Strasbourg University Hospital, CEDEX, 67098 Strasbourg, France; (D.R.); (E.P.); (E.G.); (L.D.); (V.R.); (A.-C.V.); (L.V.)
- Bio-imagery and Pathology (LBP), UMR CNRS 7021, Strasbourg University, 67400 Illkirch-Graffenstaden, France
| | - Lucile Pabst
- Department of Pneumology, Strasbourg University Hospital, CEDEX, 67091 Strasbourg, France; (L.P.); (C.M.)
| | - Erwan Pencreach
- Department of Biochemistry and Molecular Biology, Strasbourg University Hospital, CEDEX, 67098 Strasbourg, France; (D.R.); (E.P.); (E.G.); (L.D.); (V.R.); (A.-C.V.); (L.V.)
- INSERM U1113, IRFAC, Strasbourg University, 67000 Strasbourg, France
| | - Eric Guérin
- Department of Biochemistry and Molecular Biology, Strasbourg University Hospital, CEDEX, 67098 Strasbourg, France; (D.R.); (E.P.); (E.G.); (L.D.); (V.R.); (A.-C.V.); (L.V.)
- INSERM U1113, IRFAC, Strasbourg University, 67000 Strasbourg, France
| | - Laurent Dano
- Department of Biochemistry and Molecular Biology, Strasbourg University Hospital, CEDEX, 67098 Strasbourg, France; (D.R.); (E.P.); (E.G.); (L.D.); (V.R.); (A.-C.V.); (L.V.)
| | - Valérie Rimelen
- Department of Biochemistry and Molecular Biology, Strasbourg University Hospital, CEDEX, 67098 Strasbourg, France; (D.R.); (E.P.); (E.G.); (L.D.); (V.R.); (A.-C.V.); (L.V.)
| | - Anne-Claire Voegeli
- Department of Biochemistry and Molecular Biology, Strasbourg University Hospital, CEDEX, 67098 Strasbourg, France; (D.R.); (E.P.); (E.G.); (L.D.); (V.R.); (A.-C.V.); (L.V.)
| | - Laurent Vallat
- Department of Biochemistry and Molecular Biology, Strasbourg University Hospital, CEDEX, 67098 Strasbourg, France; (D.R.); (E.P.); (E.G.); (L.D.); (V.R.); (A.-C.V.); (L.V.)
| | - Céline Mascaux
- Department of Pneumology, Strasbourg University Hospital, CEDEX, 67091 Strasbourg, France; (L.P.); (C.M.)
- INSERM U1113, IRFAC, Strasbourg University, 67000 Strasbourg, France
| | - Michèle Beau-Faller
- Department of Biochemistry and Molecular Biology, Strasbourg University Hospital, CEDEX, 67098 Strasbourg, France; (D.R.); (E.P.); (E.G.); (L.D.); (V.R.); (A.-C.V.); (L.V.)
- INSERM U1113, IRFAC, Strasbourg University, 67000 Strasbourg, France
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Novel, selective acrylamide linked quinazolines for the treatment of double mutant EGFR-L858R/T790M Non-Small-Cell lung cancer (NSCLC). Bioorg Chem 2021; 115:105234. [PMID: 34399322 DOI: 10.1016/j.bioorg.2021.105234] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 06/21/2021] [Accepted: 07/29/2021] [Indexed: 01/02/2023]
Abstract
T790M mutation is the most common mechanism of acquired resistance to first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). To overcome this resistance, 4-anilinoquinazoline-based irreversible inhibitors afatinib, dacomitinib has been developed. However, the clinical application of these irreversible inhibitors is limited due to its narrow selectivity against L858R/T790M mutant EGFR. In an attempt to develop potent and selective EGFR T790M inhibitors, we have designed and synthesized two series of novel acrylamide linked quinazolines. Among them, compounds 2i (IC50 0.171 µM) and 11h (IC50 0.159 µM) were identified as potent compounds, which displayed selective and potent anti-proliferative activity on gefitinib-resistant cell line NCI-H1975 as compared to the gefitinib and WZ4002 in cellular assay. Furthermore, a molecular dynamic simulation of 11h was carried out to assess the stability to form a complex with the L858R/T790M EGFR Kinase domain, which demonstrated that complex was stable for the 100 ns and form strong crucial covalent binding contacts with the thiol group of Cys797 residue. Finally, satisfactory in silico pharmacokinetics properties of 2i, 11h and 11i compounds were predicted. The synthesized compounds were also evaluated for in vitro cytotoxic activity/hepatotoxicity against HepG2 cell line through MTT assay. The results revealed that compounds exhibited lower cytotoxicity to HepG2 cells.
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Zhou C, Xie L, Liu W, Zhang L, Zhou S, Wang L, Chen J, Li H, Zhao Y, Zhu B, Ding S, Zhang C, Shao F. Absorption, metabolism, excretion, and safety of [ 14C]almonertinib in healthy Chinese subjects. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:867. [PMID: 34164501 PMCID: PMC8184462 DOI: 10.21037/atm-21-1606] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Background Almonertinib Mesilate Tablets (HS-10296, Hansoh Pharma, Shanghai, China) is a novel and selective third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). A phase I study of almonertinib in patients with non-small cell lung cancer (NSCLC) demonstrated a linear metabolic trend, a good tolerability/safety profile, and preliminary antitumor activity. However, the metabolism, excretion, and substance balance of almonertinib has not been clearly determined. Here, we investigated the pharmacokinetic characteristics and safety profile of almonertinib following a single oral dose (110 mg/50 µCi) in healthy Chinese male participants. Methods Total radioactivity (TRA) in whole blood, plasma, urine, and feces was measured by utilizing a liquid scintillation counter to obtain almonertinib substance balance data. The pharmacokinetic parameters of [14C]almonertinib and the parent drug almonertinib in whole blood and plasma were analyzed with noncompartmental analysis in the WinNonlin software (Pharsight Corp). The major metabolites in plasma, urine, and feces were analyzed by high-performance liquid chromatography (HPLC) coupled with an online or offline isotope detector. The safety of the drug was evaluated after administration. Results The safety and tolerability of a single oral dose of 110 mg/50 µCi [14C] almonertinib suspension were good in healthy Chinese male participants. There was no significant abnormality or special adverse reaction. TRA peaked quickly in plasma, with a Tmax of 4.0 h; however, TRA was cleared slowly in vivo, with a mean terminal elimination phase (half-life, T1/2) of up to 863 h. In addition to the parent drug, a total of 26 metabolites in blood, urine, and feces were analyzed. In plasma, parent drug was the major drug-related component, accounting for 69.97% of TRA, and M440 (almonertinib-M2 demethyl product) was the major metabolite, accounting for 5.08% of TRA; in urine, parent drug accounted for 0.48% of the dose administered and HAS-719 was the major metabolite, accounting for 1.20% of the administered dose; in feces, parent drug was about 8.61% of the dose administered and HAS-719 was the major metabolite, accounting for 12.33% of the administered dose, which was followed by M541a/M470a and M617/M575, accounting for 11.8% and 6.76% of the administered dose, respectively. Conclusions Almonertinib has a good safety profile, with parent drug as its main circulating component. almonertinib is extensively metabolized in vivo before excretion and is excreted as a parent drug and metabolites mainly via feces. Trial registration The trial registration number: CTR20192291.
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Affiliation(s)
- Chen Zhou
- Phase I Clinical Trial Unit, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Lijun Xie
- Phase I Clinical Trial Unit, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Wei Liu
- Nuclear Medicine Department, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Lingling Zhang
- Lab Testing Division, Department of DMPK Service, WuXi AppTec Co., Ltd., Nanjing, China
| | - Sufeng Zhou
- Phase I Clinical Trial Unit, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Lu Wang
- Phase I Clinical Trial Unit, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Juan Chen
- Phase I Clinical Trial Unit, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Huan Li
- Lab Testing Division, Department of DMPK Service, WuXi AppTec Co., Ltd., Nanjing, China
| | - Yuqing Zhao
- Phase I Clinical Trial Unit, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Bei Zhu
- Phase I Clinical Trial Unit, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Sijia Ding
- Phase I Clinical Trial Unit, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Chen Zhang
- Nuclear Medicine Department, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Feng Shao
- Phase I Clinical Trial Unit, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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Wu Z, Chen S, Du X, Wu Y, Xie X. Hepatotoxicity with epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer patients: A network meta-analysis. J Clin Pharm Ther 2021; 46:310-318. [PMID: 33031574 DOI: 10.1111/jcpt.13281] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Revised: 08/23/2020] [Accepted: 09/07/2020] [Indexed: 01/16/2023]
Abstract
WHAT IS KNOWN AND OBJECTIVE The efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in patients diagnosed with non-small-cell lung cancer (NSCLC) has been confirmed by a large number of studies. However, hepatotoxicity caused by EGFR-TKIs has not been widely investigated. This review compares the hepatotoxicity of different EGFR-TKIs through a network meta-analysis. METHODS PubMed, EMBASE, Cochrane Library and ClinicalTrials.gov were systematically searched from their individual inceptions to 20 May 2020 with the goal of identifying randomized controlled trials (RCTs) reporting hepatotoxicity in NSCLC patients receiving EGFR-TKIs. A random-effects pairwise meta-analysis and network meta-analysis were performed within a frequentist framework. Risk ratios (RRs) and 95% confidence intervals (CIs) were calculated. RESULTS Twelve eligible RCTs, including data from 6,280 patients diagnosed with NSCLC, were analysed. In our network meta-analysis, gefitinib was associated with a higher risk for hepatotoxicity compared to placebo (RR, 2.55; 95% CI, 1.32-4.89) and dacomitinib (RR, 2.60; 95% CI, 1.30-5.20) in terms of all-grades alanine transaminase (ALT) elevation. As for all-grades aspartate transaminase (AST) elevation, gefitinib and erlotinib showed a significantly increased risk for hepatotoxicity compared to afatinib, dacomitinib and placebo (erlotinib vs. afatinib: RR, 1.85; 95% CI, 1.05-3.24; erlotinib vs. dacomitinib: RR, 1.68; 95% CI, 1.19-2.36; erlotinib vs. placebo: RR, 3.38; 95% CI, 1.69-6.73; gefitinib vs. afatinib: RR, 2.23; 95% CI, 1.32-3.79; gefitinib vs. dacomitinib: RR, 2.03; 95% CI, 1.51-2.73; gefitinib vs. placebo: RR, 4.08; 95% CI, 2.11-7.91). There was a high risk of high-grade ALT elevation in patients treated with gefitinib compared to patients treated with erlotinib (RR, 4.31; 95% CI, 2.15-8.66), dacomitinib (RR, 6.95; 95% CI, 1.85-26.05) or placebo (RR, 8.38; 95% CI, 1.56-45.01). No statistically significant differences were identified among the five agents analysed in terms of all-grades TB elevation and high-grade AST elevation. The surface under the cumulative ranking curve (SUCRA) revealed that gefitinib showed a potentially higher risk for ALT and AST elevation compared to other EGFR-TKIs regardless of grade. WHAT IS NEW AND CONCLUSION Current evidence indicates that the association between afatinib or dacomitinib and risk of liver enzyme elevation remains uncertain in patients diagnosed with NSCLC. Some evidence suggests that gefitinib and erlotinib may be associated with a significantly increased risk for hepatotoxicity in patients with NSCLC. However, given that the elevation of liver enzymes was not definitely associated with EGFR-TKIs and publication bias, further studies are required to confirm these results.
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Affiliation(s)
- Ziyang Wu
- Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | - Suhua Chen
- Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | - Xin Du
- Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | - Yibo Wu
- Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | - Xiaohui Xie
- Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University, Beijing, China
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Zhao Y, Cheng B, Chen Z, Li J, Liang H, Chen Y, Zhu F, Li C, Xu K, Xiong S, Lu W, Chen Z, Zhong R, Zhao S, Xie Z, Liu J, Liang W, He J. Toxicity profile of epidermal growth factor receptor tyrosine kinase inhibitors for patients with lung cancer: A systematic review and network meta-analysis. Crit Rev Oncol Hematol 2021; 160:103305. [PMID: 33757838 DOI: 10.1016/j.critrevonc.2021.103305] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 03/16/2021] [Accepted: 03/16/2021] [Indexed: 12/24/2022] Open
Abstract
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are treatments commonly used for lung cancer. The toxicity profile including toxicity incidence, severity, and spectrum (involving various specific adverse events) of each EGFR-TKI are of particular clinical interest and importance. Data from phase II and III randomized controlled trials comparing treatments among EGFR-TKIs (osimertinib, dacomitinib, afatinib, erlotinib, gefitinib, and icotinib) and chemotherapy for lung cancer were synthesized with Bayesian network meta-analysis. The primary outcome was systemic all-grade and grade ≥3 adverse events. The secondary outcome was specific all-grade adverse events including those of the skin, gastrointestinal tract, lung, etc. 40 trials randomizing 13,352 patients were included. Generally greater toxicity for dacomitinib and afatinib, and safety for icotinib were suggested. Furthermore, we found individual EGFR-TKIs had different toxicity spectrums. These findings provide a compelling safety reference for the individualized use of EGFR-TKIs for patients with lung cancer.
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Affiliation(s)
- Yi Zhao
- Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou 510120, China
| | - Bo Cheng
- Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou 510120, China
| | - Zisheng Chen
- Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou 510120, China; Department of Respiratory Medicine, The Sixth Affliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan 511518, China
| | - Jianfu Li
- Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou 510120, China
| | - Hengrui Liang
- Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou 510120, China
| | - Ying Chen
- Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou 510120, China
| | - Feng Zhu
- Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou 510120, China
| | - Caichen Li
- Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou 510120, China
| | - Ke Xu
- Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou 510120, China
| | - Shan Xiong
- Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou 510120, China
| | - Weixiang Lu
- Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou 510120, China
| | - Zhuxing Chen
- Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou 510120, China
| | - Ran Zhong
- Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou 510120, China
| | - Shen Zhao
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510050, China
| | - Zhanhong Xie
- Department of Respiratory Medicine, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou 510120, China
| | - Jun Liu
- Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou 510120, China
| | - Wenhua Liang
- Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou 510120, China; Department of Medical Oncology, The First People's Hospital of Zhaoqing, Zhaoqing 526020, China.
| | - Jianxing He
- Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou 510120, China.
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Sun X, Xu S, Yang Z, Zheng P, Zhu W. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors for the treatment of non-small cell lung cancer: a patent review (2014-present). Expert Opin Ther Pat 2020; 31:223-238. [PMID: 33315482 DOI: 10.1080/13543776.2021.1860210] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Introduction: EGFR is the receptor for epidermal growth factor (EGF) and belongs to the protein tyrosine kinase (PTK) receptor. It is closely related to the inhibition of tumor cell proliferation, invasion, and apoptosis. Overexpression or mutation activation of EGFR is involved in the development of many human malignancies, especially non-small cell lung cancer (NSCLC). At present, numerous small molecule tyrosine kinase inhibitors (TKIs) have been developed to target the ATP-binding region of EGFR, aiming to develop selective and effective inhibitors for the treatment of NSCLC against EGFR mutants.Areas covered: This review covers the latest progress in the patented EGFR inhibitors and the inhibition activity against NSCLC from 2014 to present.Expert opinion: EGFR is an important anti-tumor target, and small molecule inhibitors targeting EGFR have become important biologically active compounds for the treatment of cancer, especially against NSCLC. Among the recent patents available, great majority of them focus on selective inhibitors of EGFR mutants. Although great achievements have been made in the development of selective EGFR inhibitors, there is still an urgent need to discover new EGFR inhibitors which are safe, efficient, selective, and low-toxic to avoid the adverse pharmacokinetics caused by wild-type EGFR feature.
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Affiliation(s)
- Xin Sun
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, Jiangxi, China
| | - Shan Xu
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, Jiangxi, China
| | - Zunhua Yang
- College of Pharmacy, Jiangxi University of Traditional Chinese Medicine, Nanchang, China
| | - Pengwu Zheng
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, Jiangxi, China
| | - Wufu Zhu
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, Jiangxi, China
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24
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Singh SS, Dahal A, Shrestha L, Jois SD. Genotype Driven Therapy for Non-Small Cell Lung Cancer: Resistance, Pan Inhibitors and Immunotherapy. Curr Med Chem 2020; 27:5274-5316. [PMID: 30854949 DOI: 10.2174/0929867326666190222183219] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Revised: 01/25/2019] [Accepted: 02/14/2019] [Indexed: 12/14/2022]
Abstract
Eighty-five percent of patients with lung cancer present with Non-small Cell Lung Cancer (NSCLC). Targeted therapy approaches are promising treatments for lung cancer. However, despite the development of targeted therapies using Tyrosine Kinase Inhibitors (TKI) as well as monoclonal antibodies, the five-year relative survival rate for lung cancer patients is still only 18%, and patients inevitably become resistant to therapy. Mutations in Kirsten Ras Sarcoma viral homolog (KRAS) and epidermal growth factor receptor (EGFR) are the two most common genetic events in lung adenocarcinoma; they account for 25% and 20% of cases, respectively. Anaplastic Lymphoma Kinase (ALK) is a transmembrane receptor tyrosine kinase, and ALK rearrangements are responsible for 3-7% of NSCLC, predominantly of the adenocarcinoma subtype, and occur in a mutually exclusive manner with KRAS and EGFR mutations. Among drug-resistant NSCLC patients, nearly half exhibit the T790M mutation in exon 20 of EGFR. This review focuses on some basic aspects of molecules involved in NSCLC, the development of resistance to treatments in NSCLC, and advances in lung cancer therapy in the past ten years. Some recent developments such as PD-1-PD-L1 checkpoint-based immunotherapy for NSCLC are also covered.
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Affiliation(s)
- Sitanshu S Singh
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe LA 71201, United States
| | - Achyut Dahal
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe LA 71201, United States
| | - Leeza Shrestha
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe LA 71201, United States
| | - Seetharama D Jois
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe LA 71201, United States
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25
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Lee CS, Sharma S, Miao E, Mensah C, Sullivan K, Seetharamu N. A Comprehensive Review of Contemporary Literature for Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer and Their Toxicity. LUNG CANCER (AUCKLAND, N.Z.) 2020; 11:73-103. [PMID: 33117017 PMCID: PMC7548332 DOI: 10.2147/lctt.s258444] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Accepted: 08/26/2020] [Indexed: 01/10/2023]
Abstract
Mutations in the epidermal growth factor receptor (EGFR) are common amongst those with non-small cell lung cancer and represent a major factor in treatment decisions, most notably in the advanced stages. Small molecule tyrosine kinase inhibitors (TKIs) that target the EGFR, such as erlotinib, gefitinib, icotinib, afatinib, dacomitinib and osimertinib, have all shown to be effective in this setting. Osimertinib, a third-generation EGFR TKI, is a favorable option, but almost all patients develop resistance at some time point. There are no effective treatment options for patients who progress on osimertinib, but ongoing trials will hopefully address this unmet need. The aim of this review is to provide a comprehensive review of the data with EGFR TKIs, management of the toxicities and the ongoing trials with this class of agents.
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Affiliation(s)
- Chung-Shien Lee
- Department of Clinical Health Professions, St. John’s University, College of Pharmacy and Health Sciences, Queens, NY11439, USA
- Division of Medical Oncology and Hematology, Northwell Health Cancer Institute, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Lake Success, NY11042, USA
| | - Sandhya Sharma
- Department of Hematology and Oncology, Denver Health, Denver, CO80204, USA
| | - Emily Miao
- Albert Einstein College of Medicine, Bronx, NY, USA
| | - Cheryl Mensah
- Weil Cornell School of Medicine, Department of Hematology and Oncology, Weill Cornell of Medicine, New York, NY, USA
| | - Kevin Sullivan
- Division of Medical Oncology and Hematology, Northwell Health Cancer Institute, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Lake Success, NY11042, USA
| | - Nagashree Seetharamu
- Division of Medical Oncology and Hematology, Northwell Health Cancer Institute, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Lake Success, NY11042, USA
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Xie X, Wang X, Wu S, Yang H, Liu J, Chen H, Ding Y, Ling L, Lin H. Fatal toxic effects related to EGFR tyrosine kinase inhibitors based on 53 cohorts with 9,569 participants. J Thorac Dis 2020; 12:4057-4069. [PMID: 32944317 PMCID: PMC7475571 DOI: 10.21037/jtd-19-4000a] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Background To estimate the incidence and susceptible factors of fatal toxic effects related to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Methods PubMed and Embase were thoroughly searched for clinical trials based on the following terms and corresponding Medical Subject Heading ones: “erlotinib”, “gefitinib”, “afatinib”, “dacomitinib”, “osimertinib”, and “non-small-cell lung cancer (NSCLC)”. A total of 53 eligible cohorts with 9,569 participants were collected. Results A total of 105 cases of fatal toxic effects related to EGFR-TKIs occurred in 53 cohorts. The overall incidence was 1.33% [95% confidence interval (CI): 1.08–1.63%]. The odds and incidence were apparently higher in Japanese group (compared with non-East Asian group) [2.72 vs. 1.30, P=0.015; odds ratio (OR): 2.26, 95% CI: 1.17–4.37, P=0.015], in first-line treatment group (compared with EGFR-TKI retreatment group) (1.54 vs. 0.69, P=0.028; OR: 2.41, 95% CI: 1.10–5.26, P=0.028), and in the trial phase II (compared with trial phase III) (1.82% vs. 1.11%, P=0.009; OR: 1.73, 95% CI: 1.15–2.62, P=0.009). Notably, the Japanese group was higher than non-East Asian group after controlling for the treatment-line and trial phase (OR: 2.16, 95% CI: 1.12–4.16, P=0.022). Interstitial lung disease (ILD) was predominant in 29 fatal causes followed by pneumonia, respiratory failure and diarrhea. Conclusions The overall incidence of fatal toxic effects related to EGFR-TKIs was 1.33%, and the major fatal cause was ILD, followed by pneumonia, respiratory failure and diarrhea. The susceptible factor of fatal toxic effects related to EGFR-TKIs was the Japanese group. This study provided a capability for clinicians to predict and detect high-risk populations of fatal toxic effects.
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Affiliation(s)
- Xianhe Xie
- Department of Chemotherapy, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Xuewen Wang
- Department of Oncology, The 900th Hospital of the People's Liberation Army Joint Service Support Force, Fuzong Clinical Medical College of Fujian Medical University, Fuzhou, China
| | - Sumei Wu
- Department of Chemotherapy, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Haitao Yang
- Department of Chemotherapy, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Junjin Liu
- Department of Chemotherapy, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Huijuan Chen
- Department of Chemotherapy, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Yin Ding
- Department of Chemotherapy, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Liting Ling
- Department of Chemotherapy, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Heng Lin
- Department of Chemotherapy, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
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KRAS mutation as a prognostic factor and predictive factor in advanced/metastatic non-small cell lung cancer: A systematic literature review and meta-analysis. Cancer Treat Res Commun 2020; 24:100200. [PMID: 32750661 DOI: 10.1016/j.ctarc.2020.100200] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Revised: 07/21/2020] [Accepted: 07/23/2020] [Indexed: 01/08/2023]
Abstract
KRAS (Kirsten Rat Sarcoma) is the most common oncogenic mutation detected in patients with non-small cell lung cancer (NSCLC). However, the role of KRAS as either a prognostic factor or predictive factor (modifier of treatment effects) in NSCLC is not well established at this time. This systematic literature review (SLR) and meta-analysis synthesized the available evidence regarding the role of KRAS mutation as a predictive factor and/or prognostic factor of survival and response outcomes in patients with advanced/metastatic (stage IIIB-IV) NSCLC. Relevant clinical trials and observational studies were identified by searching MEDLINE, Embase and Cochrane Register of Controlled Trials. Meta-analyses were performed using data extracted from multivariable and univariable analyses from clinical studies to assess the empirical evidence of KRAS mutation status as a prognostic or/and predicitive factor. 43 selected studies were identified by the SLR and included in this meta-analysis. Pairwise meta-analyses of hazard ratios (HRs) reported in randomized controlled trials (RCTs) did not demonstrate a significant prognostic effect of mutant KRAS on overall survival (OS) (HR=1.10; 95% CI [0.88, 1.38]) or progression free survival (PFS) (HR=1.03; 95% CI [0.80, 1.33]). However, when conducting meta-analyses on HRs reported in observational studies, a statistically significant negative prognostic effect of mutant KRAS was observed (OS HR=1.71; 95% CI [1.07, 2.84]; PFS HR=1.18; 95% CI [1.02, 1.36]). Meta-analyses of objective response rate (ORR) in RCTs demonstrated a negative prognostic effect of mutant KRAS (RR=0.38; 95% CI [0.16, 0.63]). Limited data were available to evaluate the role of KRAS mutation as a predictive factor. In conclusion, this research offers evidence that KRAS mutation may be a negative prognostic factor for survival and response outcomes in patients with advanced/metastatic NSCLC, but further research is needed to address conflicting results on the importance of KRAS mutations as a predictive factor.
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Peng YM, Duan H, Zhang J, Sun C, Zhang X, Shen W, Zheng S, Tan K, Jiang X, Li J, Cui HJ. Application of Zizao Yangrong Granules for Treating Targeted Drugs-Related Skin Xerosis: A Randomized Double-Blinded Controlled Study. Integr Cancer Ther 2020; 19:1534735420924832. [PMID: 32567372 PMCID: PMC7309378 DOI: 10.1177/1534735420924832] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Background: Dermatologic toxicities are the most common side effects associated with the targeted drugs epidermal growth factor receptor inhibitors (EGFRIs), in which xerosis commonly complicated by pruritus severely disturbs the quality of life. The study has observed the curative effect of Zizao Yangrong granules (ZYG) from Chishui Xuanzhu in the treatment of EGFRIs-related xerosis and pruritus, as well as evaluating the safety of the prescription. Methods: Patients (n = 68) who had xerosis after using EGFRIs were enrolled and then randomly divided into the treatment group and control group, respectively, receiving ZYG and placebo granules combined with vitamin E ointment. The intervention lasted 4 weeks. Changes in xerosis and pruritus were observed, and blood routine examination as well as liver and kidney function are observed as safety indexes. The water content of skin and qualify of life were observed. Results: A total of 66 out of 68 patients finished the study with 34 patients in each group. The effective rates of xerosis among the treatment group and control group were 84.8% and 69.7% after 2 weeks’ treatment (P < .05), while they were 84.8% and 75.8% after 4 weeks’ treatment (P < .05). The patients in the experimental group had better quality of life than that in the control group (P = .045). Conclusion: ZYG can effectively improve the skin dryness associated with EGFRIs, and significantly improve the quality of life of patients with good safety; however, larger randomized controlled trials are needed to verify these findings.
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Affiliation(s)
- Yan Mei Peng
- Fangshan Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Hua Duan
- Beijing University of Chinese Medicine, Beijing, China
| | - Jingyi Zhang
- Beijing University of Chinese Medicine, Beijing, China
| | - Chenyao Sun
- Beijing University of Chinese Medicine, Beijing, China
| | - Xu Zhang
- Beijing University of Chinese Medicine, Beijing, China
| | - Wen Shen
- Beijing University of Chinese Medicine, Beijing, China
| | - Shuyue Zheng
- Beijing University of Chinese Medicine, Beijing, China
| | - Kexin Tan
- Beijing University of Chinese Medicine, Beijing, China
| | - Xuejiao Jiang
- Beijing University of Chinese Medicine, Beijing, China
| | - Jia Li
- Beijing University of Chinese Medicine, Beijing, China
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29
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Chi AS, Cahill DP, Reardon DA, Wen PY, Mikkelsen T, Peereboom DM, Wong ET, Gerstner ER, Dietrich J, Plotkin SR, Norden AD, Lee EQ, Nayak L, Tanaka S, Wakimoto H, Lelic N, Koerner MV, Klofas LK, Bertalan MS, Arrillaga-Romany IC, Betensky RA, Curry WT, Borger DR, Balaj L, Kitchen RR, Chakrabortty SK, Valentino MD, Skog J, Breakefield XO, Iafrate AJ, Batchelor TT. Exploring Predictors of Response to Dacomitinib in EGFR-Amplified Recurrent Glioblastoma. JCO Precis Oncol 2020; 4:1900295. [PMID: 32923886 DOI: 10.1200/po.19.00295] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/10/2020] [Indexed: 01/16/2023] Open
Abstract
PURPOSE Despite the high frequency of EGFR genetic alterations in glioblastoma (GBM), EGFR-targeted therapies have not had success in this disease. To improve the likelihood of efficacy, we targeted adult patients with recurrent GBM enriched for EGFR gene amplification, which occurs in approximately half of GBM, with dacomitinib, a second-generation, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that penetrates the blood-brain barrier, in a multicenter phase II trial. PATIENTS AND METHODS We retrospectively explored whether previously described EGFR extracellular domain (ECD)-sensitizing mutations in the context of EGFR gene amplification could predict response to dacomitinib, and in a predefined subset of patients, we measured post-treatment intratumoral dacomitinib levels to verify tumor penetration. RESULTS We found that dacomitinib effectively penetrates contrast-enhancing GBM tumors. Among all 56 treated patients, 8 (14.3%) had a clinical benefit as defined by a duration of treatment of at least 6 months, of whom 5 (8.9%) remained progression free for at least 1 year. Presence of EGFRvIII or EGFR ECD missense mutation was not associated with clinical benefit. We evaluated the pretreatment transcriptome in circulating extracellular vesicles (EVs) by RNA sequencing in a subset of patients and identified a signature that distinguished patients who had durable benefit versus those with rapid progression. CONCLUSION While dacomitinib was not effective in most patients with EGFR-amplified GBM, a subset experienced a durable, clinically meaningful benefit. Moreover, EGFRvIII and EGFR ECD mutation status in archival tumors did not predict clinical benefit. RNA signatures in circulating EVs may warrant investigation as biomarkers of dacomitinib efficacy in GBM.
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Affiliation(s)
- Andrew S Chi
- Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - Daniel P Cahill
- Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - David A Reardon
- Dana-Farber/Brigham and Women's Cancer Center and Harvard Medical School, Boston, MA
| | - Patrick Y Wen
- Dana-Farber/Brigham and Women's Cancer Center and Harvard Medical School, Boston, MA
| | - Tom Mikkelsen
- Ontario Brain Institute, Toronto, Ontario, Canada.,Henry Ford Hospital, Detroit, MI
| | | | - Eric T Wong
- Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA
| | | | - Jorg Dietrich
- Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - Scott R Plotkin
- Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - Andrew D Norden
- Dana-Farber/Brigham and Women's Cancer Center and Harvard Medical School, Boston, MA
| | - Eudocia Q Lee
- Dana-Farber/Brigham and Women's Cancer Center and Harvard Medical School, Boston, MA
| | - Lakshmi Nayak
- Dana-Farber/Brigham and Women's Cancer Center and Harvard Medical School, Boston, MA
| | - Shota Tanaka
- Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - Hiroaki Wakimoto
- Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - Nina Lelic
- Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - Mara V Koerner
- Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - Lindsay K Klofas
- Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - Mia S Bertalan
- Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | | | | | - William T Curry
- Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - Darrel R Borger
- Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - Leonora Balaj
- Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | | | | | | | | | | | - A John Iafrate
- Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - Tracy T Batchelor
- Massachusetts General Hospital and Harvard Medical School, Boston, MA
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Han C, Ren J, Su F, Hu X, Li M, Wang Z, Wu L. Hybrids of Quinoline and Anilinopyrimidine: Novel EGFRT790M Inhibitors with Antiproliferative Activity against Non-Small Cell Lung Cancer Cell Lines. Anticancer Agents Med Chem 2020; 20:724-733. [PMID: 32116203 DOI: 10.2174/1871520620666200302113206] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 10/24/2019] [Accepted: 01/27/2020] [Indexed: 12/30/2022]
Abstract
BACKGROUND The third-generation irreversible Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors (TKIs) inhibit the T790M mutation while sparing EGFRWT. However, the C797S point mutation confers resistance to existing irreversible EGFRT790M inhibitors. OBJECTIVE Novel EGFRT790M inhibitors were designed through hybridization of quinoline and anilinopyrimidine, and biologically evaluated their antiproliferative activity against Non-Small Cell Lung Cancer (NSCLC) cell lines. METHODS The target compounds 11a-h were synthesized and structurally characterized with 1H, 13C Nuclear Magnetic Resonance (NMR) spectroscopy and High-Resolution Mass Spectrometry (HRMS). Their inhibitory effects on tumor cell proliferation and EGFR kinase were biologically evaluated. Additionally, molecular docking studies were also performed on the representative typical EGFRT790M inhibitor. RESULTS Most of the evaluated compounds displayed moderate antiproliferative activity on H1975 cells with EGFRL858R/T790M. However, compound 11a (IC50 = 2.235 ± 0.565μM) showed stronger inhibition than gefitinib (IC50 = 8.830 ± 0.495μM) in concentration- and time-dependent manner. Moreover, compound 11a exhibited weaker inhibitory activities on cells with EGFRWT. Specifically, compound 11a strongly suppressed EGFRL858R/T790M (IC50 = 0.515 ± 0.011μM) relative to EGFRWT (IC50 = 0.913 ± 0.068μM). Furthermore, molecular docking studies demonstrated its strong binding contacts with the EGFRT790M enzyme through hydrogen bonds and other non-bonded interactions. CONCLUSION Taken together, these results indicate that the hybrid of quinoline and anilinopyrimidine 11a, could be a potential inhibitor of EGFRT790M in NSCLC, which warrants further in-depth studies.
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Affiliation(s)
- Chun Han
- Department of Chemistry, Changzhi University, Shanxi, Changzhi 046011, China
| | - Jiahong Ren
- Department of Biology, Changzhi University, Shanxi, Changzhi 046011, China
| | - Feng Su
- Department of Chemistry, Changzhi University, Shanxi, Changzhi 046011, China
| | - Xiaoqin Hu
- Department of Chemistry, Changzhi University, Shanxi, Changzhi 046011, China
| | - Mengyao Li
- Department of Chemistry, Changzhi University, Shanxi, Changzhi 046011, China
| | - Zhijun Wang
- Department of Chemistry, Changzhi University, Shanxi, Changzhi 046011, China
| | - Lintao Wu
- Department of Chemistry, Changzhi University, Shanxi, Changzhi 046011, China
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31
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Halogenating Enzymes for Active Agent Synthesis: First Steps Are Done and Many Have to Follow. Molecules 2019; 24:molecules24214008. [PMID: 31694313 PMCID: PMC6864650 DOI: 10.3390/molecules24214008] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 10/28/2019] [Accepted: 10/31/2019] [Indexed: 12/22/2022] Open
Abstract
Halogens can be very important for active agents as vital parts of their binding mode, on the one hand, but are on the other hand instrumental in the synthesis of most active agents. However, the primary halogenating compound is molecular chlorine which has two major drawbacks, high energy consumption and hazardous handling. Nature bypassed molecular halogens and evolved at least six halogenating enzymes: Three kind of haloperoxidases, flavin-dependent halogenases as well as α-ketoglutarate and S-adenosylmethionine (SAM)-dependent halogenases. This review shows what is known today on these enzymes in terms of biocatalytic usage. The reader may understand this review as a plea for the usage of halogenating enzymes for fine chemical syntheses, but there are many steps to take until halogenating enzymes are reliable, flexible, and sustainable catalysts for halogenation.
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Lavacchi D, Mazzoni F, Giaccone G. Clinical evaluation of dacomitinib for the treatment of metastatic non-small cell lung cancer (NSCLC): current perspectives. DRUG DESIGN DEVELOPMENT AND THERAPY 2019; 13:3187-3198. [PMID: 31564835 PMCID: PMC6735534 DOI: 10.2147/dddt.s194231] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Accepted: 08/23/2019] [Indexed: 12/25/2022]
Abstract
Systemic treatment of advanced non-small cell lung cancer (NSCLC) has undergone remarkable changes in the last decade, with the introduction of targeted therapies and immunotherapy. The identification of activating mutations in the epidermal growth factor receptor (EGFR) gene (deletions in exon 19 [Del19] and point mutation L858R in exon 21) has been the first important step toward molecularly guided precision therapy in lung cancer. Several randomized trials comparing EGFR tyrosine kinase inhibitors (TKIs) (gefitinib, erlotinib, and afatinib) to standard chemotherapy in first-line treatment of advanced EGFR-mutant NSCLC showed significant improvement in progression-free survival (PFS) and in response rate, with lower rates of adverse events (AEs) and better symptom control. However, none of these trials showed significant improvement in overall survival (OS). Despite impressive responses with EGFR-TKI, disease invariably progresses after 9 to 13 months, due to acquired resistance. Dacomitinib is a potent, irreversible, highly selective, second-generation EGFR-TKI, which inhibits the signaling from both heterodimers and homodimers of all the members of the human epidermal growth factor receptor (HER) family. Here, we review the clinical development of dacomitinib from phase I to phase III, with particular attention to its toxicity and on its activity on T790M mutation. Then, we critically examine the results of ARCHER 1050, a study that was crucial for Food and Drug Administration (FDA) approval. ARCHER 1050 was the first randomized phase III study comparing dacomitinib with gefitinib, in first-line treatment of patients with advanced EGFR-mutated NSCLC. Dacomitinib was superior to gefitinib in terms of primary end-point (14.7 vs 9.2 months) and OS (34.1 vs 26.8 months). The incidence of diarrhea, skin rash, mucositis and, consequently, dose reductions was higher with dacomitinib, while hepatic toxicity was higher with gefitinib. Dacomitinib constitutes one of the standard first-line options in patients with advanced EGFR-mutated NSCLC. ![]()
Point your SmartPhone at the code above. If you have a QR code reader the video abstract will appear. Or use: https://youtu.be/nEFa8z6JeRU
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Affiliation(s)
- Daniele Lavacchi
- Department of Oncology, Careggi Hospital and University of Florence, Florence, Italy
| | - Francesca Mazzoni
- Department of Oncology, Careggi Hospital and University of Florence, Florence, Italy
| | - Giuseppe Giaccone
- Department of Oncology, Careggi Hospital and University of Florence, Florence, Italy.,Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
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33
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Van Der Weijst L, Lievens Y, Schrauwen W, Surmont V. Health-Related Quality of Life in Advanced Non-small Cell Lung Cancer: A Methodological Appraisal Based on a Systematic Literature Review. Front Oncol 2019; 9:715. [PMID: 31456938 PMCID: PMC6699450 DOI: 10.3389/fonc.2019.00715] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2019] [Accepted: 07/18/2019] [Indexed: 12/24/2022] Open
Abstract
Background: The majority of lung cancer patients are diagnosed with advanced non-small cell lung cancer (NSCLC), the bulk of which receive palliative systemic treatment with the goal to provide effective symptom palliation and safeguard health-related quality of life (HRQoL). Advanced NSCLC trials with HRQoL endpoints face methodological constraints limiting interpretability. Objectives: We provide a comprehensive overview of recent clinical trials evaluating the impact of systemic therapies on HRQoL in advanced NSCLC, focusing on the methodological quality, with the ultimate goal to improve interpretation, comparison and reporting of HRQoL data. Methods: A systematic literature review was performed. Prospective studies published over the last decade evaluating the impact of systemic treatments on HRQoL in advanced NSCLC were included. Methodological quality of HRQoL reporting was assessed with the CONSORT-PRO extension. Results: Hundred-twelve manuscripts describing 85 trials met all criteria. No formal conclusion can be drawn regarding the impact on HRQoL of different treatments. We report an important variety in methodological quality in terms of definitions of HRQoL, missing data points, lack of standardization of analyzing and presenting HRQoL and no standard follow-up time. The quality of HRQoL data reporting varies substantially between studies but improves over time. Conclusion: This review shows that in the heterogeneous landscape of trials addressing HRQoL in advanced stage NSCLC. Methodology reporting remains generally poor. Adequate reporting of HRQoL outcome data is equally important to support clinical decision-making as to correctly inform health policy regarding direct approval and reimbursement of the new drugs and combinations that will come online.
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Affiliation(s)
| | - Yolande Lievens
- Department of Radiotherapy-Oncology, Ghent University Hospital, Ghent, Belgium
| | - Wim Schrauwen
- Department of Medical Oncology, Ghent University Hospital, Ghent, Belgium
| | - Veerle Surmont
- Department of Thoracic Oncology, Ghent University Hospital, Ghent, Belgium
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34
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Santarpia M, Menis J, Chaib I, Gonzalez Cao M, Rosell R. Dacomitinib for the first-line treatment of patients with EGFR-mutated metastatic non-small cell lung cancer. Expert Rev Clin Pharmacol 2019; 12:831-840. [PMID: 31356117 DOI: 10.1080/17512433.2019.1649136] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Introduction: Different EGFR tyrosine kinase inhibitors (TKIs) are currently approved for the first-line treatment of NSCLC patients with EGFR mutations. Dacomitinib is an orally administered, second-generation pan-HER inhibitor that has shown to improve PFS and OS compared to the first-generation TKI gefitinib and is the most recent inhibitor to be approved in this setting. Areas covered: This article will review relevant literature regarding preclinical findings and clinical data from phase I-III trials of dacomitinib. We particularly discuss the mechanism of action of dacomitinib and its clinical efficacy and toxicity as a novel, first-line therapeutic option for EGFR-mutated NSCLC. Expert commentary: The therapeutic landscape for EGFR-mutated NSCLC has been greatly expanded. In the first-line setting, we have currently first-, second- and third-generation EGFR TKIs available and some combination strategies, including EGFR TKIs with anti-angiogenic drugs or chemotherapy, have also shown to be effective. However, more data are needed to define the optimal therapeutic sequencing of all these targeted agents and combinations. In this view, molecular profiling of tumor tissues and liquid biopsies may provide novel insights on mechanisms of resistance to different drugs and guide treatment decisions.
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Affiliation(s)
- Mariacarmela Santarpia
- Medical Oncology Unit, AOU Policlinico "G. Martino", Department of Human Pathology of Adult and Evolutive Age "G.Barresi", University of Messina , Messina , Italy
| | - Jessica Menis
- Division of Medical Oncology 2, Istituto Oncologico Veneto IRCCS , Padova , Italy.,Department of Surgery, Oncology and Gastroenterology, University of Padova , Padova , Italy
| | - Imane Chaib
- Catalan Institute of Oncology, Germans Trias i Pujol University Hospital , Badalona , Spain
| | - Maria Gonzalez Cao
- Dr. Rosell Oncology Institute (IOR), Dexeus University Hospital , Barcelona , Spain
| | - Rafael Rosell
- Catalan Institute of Oncology, Germans Trias i Pujol University Hospital , Badalona , Spain.,Dr. Rosell Oncology Institute (IOR), Dexeus University Hospital , Barcelona , Spain
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Abstract
The use of targeted therapy in the management of epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer is an important milestone in the management of advanced lung cancer. There are several generations of EGFR tyrosine kinase inhibitors available for clinical use. Dacomitinib is a second-generation irreversible EGFR tyrosine kinase inhibitor with early-phase clinical studies showing efficacy in non-small-cell lung cancer. In the recently published ARCHER 1050 phase III study, dacomitinib given at 45 mg/day orally was superior to gefitinib, a first-generation reversible EGFR tyrosine kinase inhibitor, in improving both progression-free survival and overall survival when given as first-line therapy. There is no prospective evidence to support the use of dacomitinib as subsequent therapy in patients previously treated with chemotherapy or a first-generation EGFR tyrosine kinase inhibitor such as gefitinib and erlotinib. Dacomitinib has not demonstrated any benefit in unselected patients with non-small-cell lung cancer, and its use should be limited to those with known EGFR-sensitizing mutations. Dacomitinib is associated with increased toxicities of diarrhea, rash, stomatitis, and paronychia compared with first-generation EGFR inhibitors. Global quality of life was maintained when assessed in phase III studies. Overall, dacomitinib is an important first- line agent in EGFR-mutated non-small-cell lung cancer in otherwise fit patients whose toxicities can be well managed.
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36
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Li W, Li Y, Zhang H, Li Y, Yuan Y, Gong H, Wei S, Liu H, Chen J. [Study on the Difference of Gene Expression between Central and Peripheral Lung Squamous Cell Carcinoma Based on TCGA Database]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2019; 22:280-288. [PMID: 31109437 PMCID: PMC6533195 DOI: 10.3779/j.issn.1009-3419.2019.05.04] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
背景与目的 肺癌是一种具有高发病率与高死亡率的恶性肿瘤疾病，最常见的类型为非小细胞肺癌（non-small cell lung cancer, NSCLC），其中肺鳞癌作为NSCLC中的一个亚型，具有特殊的病理学类型及其特定的治疗方法，根据临床表型不同又可分为周围型和中央型。本研究基于中央型和周围型肺鳞癌的临床差异进一步探索其基因水平的差异和其潜在的价值。 方法 从癌症基因组图谱（The Cancer Genome Atlas, TCGA）数据库收集肺鳞癌数据集，下载临床信息资料及基因表达谱资料。整理资料，分析临床数据及相对应的基因信息。 结果 在临床特征分析中发现，中央型肺鳞癌较周围型肺鳞癌更容易发生淋巴结转移（46.2%, 67/145 vs 28.9%, 26/90; P=0.019），而在性别、年龄、肿瘤大小、有无远处转移、TNM分期、表皮生长因子受体（epidermal growth factor receptor, EGFR）突变等方面未见明显差异。在基因表达水平分析中发现，中央型与周围型肺鳞癌具有1, 031个差异表达基因，其中，周围型与中央型相比，629个基因表达水平上调，402个基因表达水平下调。进一步富集分析显示差异表达基因主要体现在6个信号通路中，其中，刺激神经组织的配体-受体相互作用（neuroactive ligand-receptor interaction）通路是差异表达基因主要富集通路，其他差异表达基因主要与脂类代谢和糖代谢有关。相互作用网络分析显示，在表达上调差异基因中，肝细胞核因子1同源体A（hepatocyte nuclear factor 1 homeobox A, HNF1A）和细胞色素P450家族里的A亚家族发现的第四种酶（cytochrome p450 family, Cytochrome P450 3A4, CYP3A4）影响较为广泛，在表达下调差异基因中，人血清白蛋白（Albumin, ALB）与载脂蛋白A1（Apolipoprotein, APOA1）位于该作用网络的关键位置。 结论 中央型和周围型肺鳞癌患者不仅在淋巴结转移发生率上存在临床特征的差异，而且在基因表达水平亦有明显的不同。其中，HNF1A、CYP3A4、ALB、APOA1位于差异基因相互作用网络的关键位置，有可能参与调控二者的差异表型（phenotypic difference）。
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Affiliation(s)
- Weiting Li
- Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Yongwen Li
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Hongbing Zhang
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Ying Li
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Yin Yuan
- Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Hao Gong
- Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Sen Wei
- Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Hongyu Liu
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Jun Chen
- Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China.,Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin 300052, China
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Martin J, Lehmann A, Klauschen F, Hummel M, Lenze D, Grohé C, Tessmer A, Gottschalk J, Schmidt B, Pau HW, Witt C, Moegling S, Kromminga R, Jöhrens K. Clinical Impact of Rare and Compound Mutations of Epidermal Growth Factor Receptor in Patients With Non-Small-Cell Lung Cancer. Clin Lung Cancer 2019; 20:350-362.e4. [PMID: 31175009 DOI: 10.1016/j.cllc.2019.04.012] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Revised: 03/29/2019] [Accepted: 04/20/2019] [Indexed: 12/16/2022]
Abstract
BACKGROUND Standard therapy of advanced non-small-cell lung cancer harboring an activating mutation in the epidermal growth factor receptor (EGFR) gene is treatment with tyrosine kinase inhibitors (TKI). However, for rare and compound mutations of the EGFR gene, the clinical evidence of TKI therapy is still unclear. PATIENTS AND METHODS A total of 2906 lung cancer samples were analyzed for EGFR mutations during routine analysis between 2010 and 2017. The samples have been investigated by Sanger sequencing and since 2014 by next-generation sequencing. RESULTS We detected EGFR mutations in 408 specimens (14%). Among these, we found 41 samples with rare and 22 with compound mutations. In these 63 samples, 56 different rare EGFR mutations occurred. Information about the clinical outcome was available for 37. Among those with rare mutations, only one patient harboring the mutation p.G874D had disease that responded to first-generation TKI therapy. In contrast, the disease of all patients with compound mutations responded to first- or second-generation TKI therapy. Furthermore, we collected data on clinical relevance regarding TKI therapy from different databases and from an additional literature search, and only found data for 36 of the 56 detected rare mutations. CONCLUSION Information about the clinical outcome of patients with rare and compound EGFR mutations remains limited. At present, second- and third-generation TKIs are available, which may represent new treatment strategies for these patients. Therefore, it is becoming increasingly important to maintain databases concerning rare EGFR mutations.
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Affiliation(s)
- Juliane Martin
- Institute of Pathology, Charité, University Medicine Berlin, Berlin, Germany; Provitro AG, Berlin, Germany.
| | - Annika Lehmann
- Institute of Pathology, Charité, University Medicine Berlin, Berlin, Germany
| | - Frederick Klauschen
- Institute of Pathology, Charité, University Medicine Berlin, Berlin, Germany
| | - Michael Hummel
- Institute of Pathology, Charité, University Medicine Berlin, Berlin, Germany
| | - Dido Lenze
- Institute of Pathology, Charité, University Medicine Berlin, Berlin, Germany
| | | | | | - Joachim Gottschalk
- Department of Pathology and Neuropathology, Asklepios Klinik Nord, Hamburg, Germany
| | - Berndt Schmidt
- Lung Cancer Centrum, DRK-Kliniken Berlin Mitte, Berlin, Germany
| | - Hans-Wilhelm Pau
- Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Center, Rostock, Germany
| | - Christian Witt
- Department of Pneumonology and Immunology, Charité, University Medicine Berlin, Berlin, Germany
| | | | | | - Korinna Jöhrens
- Institute of Pathology, University Hospital Carl Gustav Carus, TU Dresden, Germany
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38
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Gao P, Zhang R, Li Z, Ding J, Xie J, Li J. Challenges of Providing Concordant Interpretation of Somatic Variants in Non-Small Cell Lung Cancer: A Multicenter Study. J Cancer 2019; 10:1814-1824. [PMID: 31205538 PMCID: PMC6547979 DOI: 10.7150/jca.29535] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Accepted: 02/21/2019] [Indexed: 12/13/2022] Open
Abstract
Background: Success of multiple-gene mutation tests by next-generation sequencing (NGS), associated with molecular targeting therapies for cancers, depending on the accuracy and consistency of interpreting variants. Here, we summarized reports from clinical laboratories for cases with non-small cell lung cancer (NSCLC) and discussed conflicting interpretations of somatic variants. Methods: Three mimetic DNA samples, containing six somatic mutations, were prepared based on three clinical case reports of NSCLC. Clinical reports and genetic testing questionnaires were collected from 67 laboratories enrolled in this investigation. Results: Thirty-four laboratories with correct variant results identified two variants, based on FDA approval of targeted drugs for the same tumor, consistently, with strong clinical significance, whereas the other variants were classified with conflicting interpretations. Discordant interpretations were reported for ERBB2 with three different classifications, including strong clinical significance (53.0%, 18/34), potential clinical significance (38.2%, 13/34), and unknown significance (8.8%, 3/34). In the variant therapeutic drug recommendation section, 32.4% of the laboratories (11/34) did not recommend all the available therapeutic drugs designated by the National Comprehensive Cancer Network (NCCN). In the remaining group of 33 laboratories with incorrect variant results, less correct classifications were acquired for the variants with strong clinical significance. Conclusions: Owing to numerous reasons, the interpretation of variants differed greatly, which might in turn lead to the inappropriate clinical care of patients with NSCLC. By analyzing the limitations of different databases used by laboratories, we integrated various types of databases with different levels of evidence to form a comprehensive and detailed variant interpretation pipeline, aiming to standardize the variant classification and provide accurate and sufficient therapeutic drug recommendation to clinicians for minimal-inappropriate therapeutic options.
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Affiliation(s)
- Peng Gao
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Beijing, People's Republic of China
- Graduate School, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, People's Republic of China
| | - Rui Zhang
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Beijing, People's Republic of China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, People's Republic of China
| | - Ziyang Li
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Beijing, People's Republic of China
- Graduate School, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, People's Republic of China
| | - Jiansheng Ding
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Beijing, People's Republic of China
- Graduate School, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, People's Republic of China
| | - Jiehong Xie
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Beijing, People's Republic of China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, People's Republic of China
| | - Jinming Li
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Beijing, People's Republic of China
- Graduate School, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, People's Republic of China
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Determination of BPI15086 and its metabolite in human plasma by ultra-high performance liquid chromatography-MS/MS and its application to a pharmacokinetic study. Bioanalysis 2019; 11:773-784. [PMID: 30994009 DOI: 10.4155/bio-2018-0307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Aim: BPI15086 is a potent, irreversible mutant-selective inhibitor of both EGFR (EGFR tyrosine kinase inhibitor) and the T790M resistance mutations tyrosine kinase. A simultaneous quantification method of BPI15086 and its main metabolite in human plasma using LC-MS/MS is documented and fully validated in this study. Methodology & results: Plasma samples were extracted and chromatographed on an Acquity ultra-high performance liquid chromatography BEH C18 column with a gradient elution. Detection was performed on a Sciex 5500 QTRAP® mass spectrometer using positive electrospray ionization. The results indicated that the method had excellent sensitivity and specificity. Conclusion: For the first time a sensitive and robust ultra-high performance liquid chromatography-MS/MS method was established and validated of BPI15086 in human plasma, this method was successfully applied in a first-in-human Phase I clinical trial studying the pharmacokinetics of the BPI15086 tablet in Chinese non-small-cell lung cancer patients.
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Lu W, Sun Q, Chen B, Li Y, Xu Y, Wang S. Novel agent #2714 potently inhibits lung cancer growth by suppressing cell proliferation and by inducing apoptosis in vitro and in vivo. Mol Med Rep 2019; 19:4788-4796. [PMID: 30942420 PMCID: PMC6522812 DOI: 10.3892/mmr.2019.10114] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Accepted: 03/20/2019] [Indexed: 02/05/2023] Open
Abstract
The use of small molecule compounds to inhibit cell proliferation is one of the most promising approaches in cancer therapy. In the present study, a cell viability assay, flow cytometry analysis, western blotting and mouse xenograft models were used to investigate the anticancer activities of #2714 and its underlying mechanisms in lung cancer. The present in vitro results suggested that #2714 significantly inhibited the viability of the human non-small cell lung cancer line SPC-A1 in a concentration- and time-dependent manner, with a half-maximal inhibitory concentration value of 5.54 µM after 48 h of treatment. Additionally, #2714 inhibited SPC-A1 cell proliferation via the Wnt/β-catenin pathway and by impairing mitochondrial membrane potential. The protein expression levels of Wnt 3a, Wnt 5a/b, phosphorylated (p)-β-catenin, p-glycogen synthase kinase 3β, and p-mitogen-activated protein kinase 14 were downregulated following treatment with #2714. Furthermore, using a mouse xenograft model, #2714 was identified to significantly inhibit tumor growth and to decrease cancer cell proliferation in vivo. #2714 may represent a novel effective anticancer compound targeting lung cancer cells. Additionally, #2714 was able to induce apoptosis and decrease cell proliferation in SPC-A1 cells via the Wnt/β-catenin pathway.
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Affiliation(s)
- Wenjie Lu
- School of Basic Medicine, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Qianqian Sun
- School of Basic Medicine, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Bo Chen
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, P.R. China
| | - Yan Li
- Pharmacodynamics Pharmacokinetics Early Safety Evaluation Model Animals, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Youzhi Xu
- School of Basic Medicine, Anhui Medical University, Hefei, Anhui 230032, P.R. China
| | - Siying Wang
- School of Basic Medicine, Anhui Medical University, Hefei, Anhui 230032, P.R. China
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Díaz-Serrano A, Gella P, Jiménez E, Zugazagoitia J, Paz-Ares Rodríguez L. Targeting EGFR in Lung Cancer: Current Standards and Developments. Drugs 2019; 78:893-911. [PMID: 29915896 DOI: 10.1007/s40265-018-0916-4] [Citation(s) in RCA: 67] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Lung cancer is the second most common malignant tumor and the leading cause of cancer death. Epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) is a distinct subtype of lung cancer comprising approximately 15-40% of non-squamous tumors. The development of first- and second-generation EGFR tyrosine kinase inhibitors (TKIs) has been a significant step forward in the treatment of patients with EGFR-mutant tumors, and over the last few years has been the therapy of choice in the initial management of patients with activating mutations in EGFR, with some differences in efficacy and toxicity profile. Up to 50% of patients treated with first- and second-generation TKIs develop an EGFR exon 20 T790M mutation at the time of progression. In this context, osimertinib has shown a great benefit in terms of progression-free survival (PFS) in the second-line setting, including central nervous system metastasis control. The FLAURA trial, which compared osimertinib to first-generation inhibitors as first-line therapy, showed a clear PFS advantage for osimertinib and a trend towards an increased overall survival (OS) assessed by investigator review. Although T790M mutation is the most common mechanism of resistance to first- and second-generation EGFR TKIs, other EGFR-dependent and -independent mechanisms have been described, such as HER2 and MET amplifications or BRAF and MEK mutations. Some mechanisms of resistance to osimertinib and other third-generation TKIs have also been described. Several fourth-generation TKIs, targeted drug combinations and immunotherapy strategies are under investigation to overcome resistance to EGFR TKIs in order to improve EGFR-mutant NSCLC patient outcomes.
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Affiliation(s)
- Asunción Díaz-Serrano
- Medical Oncology Department, Hospital Universitario 12 de Octubre, Avda de Córdoba s/n, 28041, Madrid, Spain
- Lung Cancer Group, Clinical Research Program, CNIO (Centro Nacional de Investigaciones Oncológicas) and Instituto de Investigación i+12, Madrid, Spain
| | - Pablo Gella
- Lung Cancer Group, Clinical Research Program, CNIO (Centro Nacional de Investigaciones Oncológicas) and Instituto de Investigación i+12, Madrid, Spain
| | - Elisabeth Jiménez
- Medical Oncology Department, Hospital Universitario 12 de Octubre, Avda de Córdoba s/n, 28041, Madrid, Spain
- Lung Cancer Group, Clinical Research Program, CNIO (Centro Nacional de Investigaciones Oncológicas) and Instituto de Investigación i+12, Madrid, Spain
| | - Jon Zugazagoitia
- Medical Oncology Department, Hospital Universitario 12 de Octubre, Avda de Córdoba s/n, 28041, Madrid, Spain
- Lung Cancer Group, Clinical Research Program, CNIO (Centro Nacional de Investigaciones Oncológicas) and Instituto de Investigación i+12, Madrid, Spain
- Yale Comprehensive Cancer Center, Yale School of Medicine, 333 Cedar Street, WWW221, New Haven, CT, 06520, USA
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - Luis Paz-Ares Rodríguez
- Medical Oncology Department, Hospital Universitario 12 de Octubre, Avda de Córdoba s/n, 28041, Madrid, Spain.
- Lung Cancer Group, Clinical Research Program, CNIO (Centro Nacional de Investigaciones Oncológicas) and Instituto de Investigación i+12, Madrid, Spain.
- Medicine School, Universidad Complutense de Madrid, Madrid, Spain.
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
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Moehler M, Maderer A, Ehrlich A, Foerster F, Schad A, Nickolay T, Ruckes C, Weinmann A, Sivanathan V, Marquardt JU, Galle PR, Woerns M, Thomaidis T. Safety and efficacy of afatinib as add-on to standard therapy of gemcitabine/cisplatin in chemotherapy-naive patients with advanced biliary tract cancer: an open-label, phase I trial with an extensive biomarker program. BMC Cancer 2019; 19:55. [PMID: 30634942 PMCID: PMC6330479 DOI: 10.1186/s12885-018-5223-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2018] [Accepted: 12/13/2018] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND To date, the cornerstone of treatment in patients with advanced or metastatic cholangiocarcinoma (CCA) is systemic chemotherapy based on a combination of gemcitabine and a platinum derivative. Other therapeutic approaches including targeted agents and tyrosine kinase inhibitors (TKI) have demonstrated disappointing results, highlighting the complexity of CCA. Recently, drugs aiming at the inhibition of HER-receptors have shown first therapeutic benefit in patients with late stage disease. The aim of this phase I study was to test the dose level toxicities (DLTs), safety and efficacy of afatinib, a highly specific panErbB family receptor TKI, in chemotherapy naive patients with advanced CCA in conjunction with an extensive biomarker program. METHODS Afatinib was administered continuously p. o. as add-on in patients with advanced CCA who received conventional chemotherapy with gemcitabine/cisplatin. A classical 3 + 3 phase I study was employed, while the maximum tolerated dose (MTD) of oral afatinib was determined in a 2 step dose escalation. Safety, overall survival (OS) and progression free survival (PFS) were evaluated for all patients. Finally, a translational biomarker analysis was conducted for the EGFR and VEGF signalling cascades. RESULTS Overall, 9 patients were enrolled. Further recruitment was discontinued due to lack of efficacy results of the tested drug in other indications. 30 mg afatinib could be safely administered as add-on to 80% of standard dose gemcitabine/cisplatin. The mOS and mPFS were 7.7 and 6.0 months, respectively. Diarrhoea and haematological disorders were the most common observed AEs. Almost all patients overexpressed EGFR on their tumour tissues, whereas none of them expressed mutations in Exons 18, 19 and 21. Non-responders showed a higher variation of VEGF-C, -D, leptin and sEGFR in their sera. CONCLUSIONS Afatinib failed to show survival benefits in combination with gemcitabine/cisplatin in patients with advanced CCA. Mutational analysis of EGFR and pathways associated with VEGF-C, -D and leptin might show promising results in future studies. CLINICAL TRIALS REGISTRATION NCT01679405 August, 2012.
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Affiliation(s)
- Markus Moehler
- I. Medical Department, Johannes-Gutenberg University, Mainz, Germany. .,Interdisciplinary Center for Clinical Trials, Johannes-Gutenberg University of Mainz, Mainz, Germany.
| | - Annett Maderer
- I. Medical Department, Johannes-Gutenberg University, Mainz, Germany
| | - Anne Ehrlich
- Interdisciplinary Center for Clinical Trials, Johannes-Gutenberg University of Mainz, Mainz, Germany
| | | | - Arno Schad
- Department of Pathology, Johannes-Gutenberg University, Mainz, Germany
| | - Tanja Nickolay
- Interdisciplinary Center for Clinical Trials, Johannes-Gutenberg University of Mainz, Mainz, Germany
| | - Christian Ruckes
- Interdisciplinary Center for Clinical Trials, Johannes-Gutenberg University of Mainz, Mainz, Germany
| | - Arndt Weinmann
- I. Medical Department, Johannes-Gutenberg University, Mainz, Germany
| | | | - Jens U Marquardt
- I. Medical Department, Johannes-Gutenberg University, Mainz, Germany
| | | | - Marcus Woerns
- I. Medical Department, Johannes-Gutenberg University, Mainz, Germany.,First Department of Medicine, University Medical Center of the Johannes-Gutenberg University Mainz, Langenbeckstr. 1, 55131, Mainz, Germany
| | - Thomas Thomaidis
- I. Medical Department, Johannes-Gutenberg University, Mainz, Germany
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Karachaliou N, Fernandez-Bruno M, Bracht JWP, Rosell R. EGFR first- and second-generation TKIs-there is still place for them in EGFR-mutant NSCLC patients. Transl Cancer Res 2019; 8:S23-S47. [PMID: 35117062 PMCID: PMC8797317 DOI: 10.21037/tcr.2018.10.06] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Accepted: 10/08/2018] [Indexed: 11/06/2022]
Abstract
Identification of epidermal growth factor receptor (EGFR) as a molecular target has radically changed the treatment of metastatic non-small cell lung cancer (NSCLC) from standard chemotherapy to personalized, targeted therapy. First-, second- and third-generation EGFR tyrosine kinase inhibitors (TKIs) are now available for the treatment of EGFR-mutant NSCLC patients. This review will focus on the clinical development of first- and second-generation EGFR TKIs. We will emphasize on essential points like the head-to-head comparison among EGFR TKIs, their activity on brain metastases, mechanisms of resistance, as well as their combination with anti-angiogenic compounds, other targeted therapies, or immunotherapy. The efficacy of first- and second-generation EGFR TKIs in early-stage EGFR-mutant NSCLC will be also finally reviewed.
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Affiliation(s)
- Niki Karachaliou
- QuironSalud Group, Institute of Oncology Rosell (IOR), University Hospital Sagrat Cor, Barcelona, Spain
- Pangaea Oncology, Laboratory of Molecular Biology, Quiron-Dexeus University Institute, Barcelona, Spain
| | - Manuel Fernandez-Bruno
- QuironSalud Group, Institute of Oncology Rosell (IOR), University Hospital Sagrat Cor, Barcelona, Spain
| | | | - Rafael Rosell
- Pangaea Oncology, Laboratory of Molecular Biology, Quiron-Dexeus University Institute, Barcelona, Spain
- Institute for Health Science Research Germans Trias i Pujol (IGTP), Badalona, Spain
- Institute of Oncology Rosell (IOR), Quiron-Dexeus University Institute, Barcelona, Spain
- Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain
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Qiu X, Lin Q, Ning Z, Qian X, Li P, Ye L, Xie S. Quantitative bioanalytical assay for the human epidermal growth factor receptor (HER) inhibitor dacomitinib in rat plasma by UPLC-MS/MS. J Pharm Biomed Anal 2018; 166:66-70. [PMID: 30612075 DOI: 10.1016/j.jpba.2018.12.041] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Revised: 12/27/2018] [Accepted: 12/27/2018] [Indexed: 02/04/2023]
Abstract
Dacomitinib is a highly selective irreversible small-molecule inhibitor of the human epidermal growth factor receptor (HER) family of tyrosine kinases. A simple and quick bioanalytical method was completely developed and validated for the assay and pharmacokinetic investigation of dacomitinib in rat plasma using ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). Proteins in 0.1 mL plasma samples were prepared by precipitant acetonitrile containing ibrutinib as the internal standard (IS). Separation of the analyte from plasma samples was carried out on an Acquity UPLC BEH C18 column using acetonitrile and 0.1% formic acid in water as mobile phase for gradient elution. The total run time and the elution time of dacomitinib were 3.0 min and 1.07 min, respectively. Positive-ion electrospray ionization (ESI) and multiple reaction monitoring (MRM) on a triple quadrupole tandem mass spectrometer were used for detection at the transitions of m/z 470.1 → 124.1 for dacomitinib and m/z 441.2 → 84.3 for ibrutinib (IS), respectively. In the range of 1-150 ng/mL, the calibration curve of dacomitinib was linear with a lower limit of quantitation (LLOQ) of 1 ng/mL. Mean recovery of dacomitinib in plasma was in the range of 76.9-84.1%. The inter- and intra-day precision (RSD) was in the scope of 1.7-8.7% and the accuracy (RE) ranged from -6.1 to 8.5%. Stability studies under different conditions were indicated to be stable. A pharmacokinetic study after oral administration of 40 mg/kg dacomitinib in rats illustrated the applicability of the new presented determination of dacomitinib.
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Affiliation(s)
- Xiangjun Qiu
- Medical College of Henan University of Science and Technology, 471003 Luoyang, PR China
| | - Qianmeng Lin
- The First Affiliated Hospital of Wenzhou Medical University, 325000 Wenzhou, PR China; School of Pharmaceutical Sciences, Wenzhou Medical University, 325000 Wenzhou, PR China
| | - Zongdi Ning
- Medical College of Henan University of Science and Technology, 471003 Luoyang, PR China
| | - Xin Qian
- Medical College of Henan University of Science and Technology, 471003 Luoyang, PR China
| | - Pengbo Li
- Medical College of Henan University of Science and Technology, 471003 Luoyang, PR China
| | - Lei Ye
- The First Affiliated Hospital of Wenzhou Medical University, 325000 Wenzhou, PR China.
| | - Saili Xie
- The First Affiliated Hospital of Wenzhou Medical University, 325000 Wenzhou, PR China.
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45
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Peng Y, Li Q, Zhang J, Shen W, Zhang X, Sun C, Cui H. Update review of skin adverse events during treatment of lung cancer and colorectal carcinoma with epidermal growth receptor factor inhibitors. Biosci Trends 2018; 12:537-552. [PMID: 30555112 DOI: 10.5582/bst.2018.01246] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
The past decades have witnessed a rapid increase in the use of molecularly targeted therapies. One class of agents includes the epidermal growth factor receptor inhibitors (EGFRIs), which afford patients longer progression-free survival (PFS) times, especially among non-small cell lung cancer (NSCLC) and metastatic colorectal carcinoma (mCRC). Certain adverse effects, particularly skin toxicity, are mainly manifested as rash, xerosis, pruritus, nails changes, hair changes and mucositis. Previous studies reported the adverse events occurred based on the cutaneous inflammation reaction. Treatment recommended glucocorticoids and antibiotics. It is suggested that skin toxicity is an important issue because it usually affects patients' quality of life (QoL) and still causes dose reduction or discontinuation of targeted therapies. For these reasons, more and more oncologists and dermatologists recognize the importance of recognition and management of skin toxicities with the expansion in availability of EGFRIs. In this review, we conducted a systematic review of recent data to examine the types and frequencies of dermatologic toxicities associated with anti-epidermal growth factor receptor (EGFR) therapies in NSCLC and mCRC. In addition, we would like to explore the management and treatment options currently used by clinicians based on the possible mechanism.
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Affiliation(s)
- Yanmei Peng
- Beijing University of Chinese Medicine, China-Japan Friendship Hospital
| | - Qiang Li
- Beijing University of Chinese Medicine, China-Japan Friendship Hospital
| | - Jingyi Zhang
- Beijing University of Chinese Medicine, China-Japan Friendship Hospital
| | - Wen Shen
- Beijing University of Chinese Medicine, China-Japan Friendship Hospital
| | - Xu Zhang
- Beijing University of Chinese Medicine, China-Japan Friendship Hospital
| | - Chenyao Sun
- Beijing University of Chinese Medicine, China-Japan Friendship Hospital
| | - Huijuan Cui
- Department of Integrative Oncology, China-Japan Friendship Hospital
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47
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Zou M, Jin B, Liu Y, Chen H, Zhang Z, Zhang C, Zhao Z, Zheng L. Synthesis and Biological Evaluation of Some Novel Thiophene-bearing Quinazoline Derivatives as EGFR Inhibitors. LETT DRUG DES DISCOV 2018. [DOI: 10.2174/1570180815666180803125935] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Background:With the approval of gefitinib, erlotinib, afatinib, and osimertinib for clinical use, targeting Epidermal Growth Factor Receptor (EGFR) has been intensively pursued. Similar to most therapies, challenges related to the treatment resistance against these drugs have emerged over time, so new EGFR Tyrosine Kinase Inhibitors (TKIs) need to be developed. This study aimed to investigate the potential use of a series of thiophene-bearing quinazoline derivatives as EGFR inhibitors. We designed and synthesized nine quinazolin derivatives, among which five compounds (5e, 5f, 5g, 5h, and 5i) were reported for the first time. </P><P> Methods: Two cancer cell lines, A431 (overexpressing EGFR) and A549 (EGFR wild-type and Kras mutation), were treated by these compounds and subjected to MTT assay. The A431 cells were selected for further treatment (5e) and Western blot analysis.Results:Although the compounds exerted no obvious effects on the proliferation of A549 cells, seven out of the nine compounds significantly inhibited the growth of A431 cells. In particular, the IC50 values of 5e and erlotinib were nearly equal. Western blot results showed that 5e significantly inhibited EGFR autophosphorylation in A431 cells. Structure-activity relationships indicated that quinazolines bearing 6,7-side chains were more potent than those unsubstituted at the 6,7-positions. Moreover, electron-withdrawing hydrophobic groups on the 5-position of the thiophene were preferred, such as chlorine or bromine atom.Conclusion:Nine 4-aminoquinazolin derivatives were designed, synthesized, and evaluated against A431 and A549 cell lines. Seven compounds significantly inhibited the growth of A431 cells. In particular, 5e possessed similar antitumor potency to that of erlotinib.
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Affiliation(s)
- Min Zou
- Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450052, China
| | - Bo Jin
- Henan Provincial Eye Hospital, Henan Provincial Peoples Hospital, Zhengzhou, 450000, China
| | - Yanrong Liu
- Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450052, China
| | - Huiping Chen
- Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450052, China
| | - Zhuangli Zhang
- Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450052, China
| | - Changzheng Zhang
- Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450052, China
| | - Zhihong Zhao
- Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450052, China
| | - Liyun Zheng
- Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450052, China
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Zhou P, Chen G, Gao M, Wu J. Design, synthesis and evaluation of the osimertinib analogue (C-005) as potent EGFR inhibitor against NSCLC. Bioorg Med Chem 2018; 26:6135-6145. [PMID: 30442506 DOI: 10.1016/j.bmc.2018.10.018] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Revised: 10/08/2018] [Accepted: 10/19/2018] [Indexed: 01/26/2023]
Abstract
Osimertinib has been approved as a first-line treatment for non-small-cell lung cancer (NSCLC) patients whose tumor carries EGFR activation and / or resistant mutations. To mitigate Osimertinib's toxicity caused by AZ5104, the N-demethylation metabolite of Osimertinib, we designed and synthesized a series of Osimertinib analogs with different headpieces. In vitro and in vivo analysis rendered a potential clinical candidate C-005 which had pyrrolo-pyridine headpiece. Biochemically, C-005 and its main human hepatocyte metabolite showed over 30 fold selectivity of L858R/T790M mutant EGFR over WT EGFR. Such selectivity profile was retained at cellular level. In general, C-005 is 2-14 fold more selective than Osimertinib in a panel of WT EGFR cancer cell lines. Furthermore, C-005 demonstrated robust antitumor efficacy and good tolerability in NCI-H1975, PC-9 and HCC827 xenograft mouse models, making it a potential candidate for human test in clinical.
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Affiliation(s)
- Ping Zhou
- Wuxi Shuangliang Biotechnology Co., Ltd., Jiangyin, Jiangsu Province 214437, People's Republic of China
| | - Gang Chen
- Nanjing Galaxy Biological Technology Co., Ltd., Nanjing, Jiangsu 210032, People's Republic of China
| | - Minqi Gao
- Wuxi Biortus Biosciences Co., Ltd., Jiangyin, Jiangsu Province 214437, People's Republic of China
| | - Jiaquan Wu
- Wuxi Shuangliang Biotechnology Co., Ltd., Jiangyin, Jiangsu Province 214437, People's Republic of China; Wuxi Biortus Biosciences Co., Ltd., Jiangyin, Jiangsu Province 214437, People's Republic of China.
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Wang M, Hu Y, Yu T, Ma X, Wei X, Wei Y. Pan-HER-targeted approach for cancer therapy: Mechanisms, recent advances and clinical prospect. Cancer Lett 2018; 439:113-130. [PMID: 30218688 DOI: 10.1016/j.canlet.2018.07.014] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Revised: 07/08/2018] [Accepted: 07/09/2018] [Indexed: 02/05/2023]
Abstract
The Human Epidermal Growth Factor Receptor family is composed of 4 structurally related receptor tyrosine kinases that are involved in many human cancers. The efficacy and safety of HER inhibitors have been compared in a wide range of clinical trials, suggesting the superior inhibitory ability of multiple- HER-targeting blockade compared with single receptor antagonists. However, many patients are currently resistant to current therapeutic treatment and novel strategies are warranted to conquer the resistance. Thus, we performed a critical review to summarize the molecular involvement of HER family receptors in tumour progression, recent anti-HER drug development based on clinical trials, and the potential resistance mechanisms of anti-HER therapy.
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Affiliation(s)
- Manni Wang
- Lab of Aging Research and Nanotoxicology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, PR China
| | - Yuzhu Hu
- Lab of Aging Research and Nanotoxicology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, PR China
| | - Ting Yu
- Lab of Aging Research and Nanotoxicology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, PR China
| | - Xuelei Ma
- Lab of Aging Research and Nanotoxicology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, PR China
| | - Xiawei Wei
- Lab of Aging Research and Nanotoxicology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, PR China.
| | - Yuquan Wei
- Lab of Aging Research and Nanotoxicology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, PR China
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Dai H, Jiao Y, Sun Z, Cao Z, Chen X. Label-free real-time ultrasensitive monitoring of non-small cell lung cancer cell interaction with drugs. BIOMEDICAL OPTICS EXPRESS 2018; 9:4149-4161. [PMID: 30615755 PMCID: PMC6157792 DOI: 10.1364/boe.9.004149] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Revised: 07/19/2018] [Accepted: 08/01/2018] [Indexed: 06/09/2023]
Abstract
The timely discovery of cancer cell resistance in clinical processing and the accurate calculation of drug dosage to reduce and inhibit tumour growth factor in cancer patients are promising technologies in cancer therapy. Here, an optofluidic resonator effectively detects drug interactions with cancer cell processing in real time and enables the calculation of label-free drug-non-small cell lung cancer (NSCLC) epidermal growth factor receptor (EGFR) and binding ratios using molecular fluorescence intensity. According to clinical test and in vivo experimental data, the efficiencies of gefitinib and erlotinib are only 37% and 12% compared to AZD9291, and 0.300 μg of EGFR inactivation requires 0.484 μg of AZD9291, 0.815 μg of gefitinib and 1.348 μg of erlotinib. Experimental results show that the present method allows for the performance detection of drug resistance and for the evaluation of dosage usage.
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Affiliation(s)
- Hailang Dai
- The State Key Laboratory on Fiber Optic Local Area Communication Networks and Advanced Optical Communication Systems, school of Physics and Astronomy, Shanghai JiaoTong University, Shanghai 200240, China
- Collaborative Innovation Center of IFSA (CICIFSA), Shanghai Jiao Tong University, Shanghai 200240, China
| | - Yihang Jiao
- The State Key Laboratory on Fiber Optic Local Area Communication Networks and Advanced Optical Communication Systems, school of Physics and Astronomy, Shanghai JiaoTong University, Shanghai 200240, China
- Collaborative Innovation Center of IFSA (CICIFSA), Shanghai Jiao Tong University, Shanghai 200240, China
| | - Zhangchi Sun
- Zhejiang Rongjun Hospital, Jiaxing 314000, China
| | - Zhuangqi Cao
- The State Key Laboratory on Fiber Optic Local Area Communication Networks and Advanced Optical Communication Systems, school of Physics and Astronomy, Shanghai JiaoTong University, Shanghai 200240, China
| | - Xianfeng Chen
- The State Key Laboratory on Fiber Optic Local Area Communication Networks and Advanced Optical Communication Systems, school of Physics and Astronomy, Shanghai JiaoTong University, Shanghai 200240, China
- Collaborative Innovation Center of IFSA (CICIFSA), Shanghai Jiao Tong University, Shanghai 200240, China
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