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Diallo MT, Chen B, Yan Z, Sun Q, Liu G, Wang Y, Ren J, Wang D. Targeted therapy for KIF3C: A study on the mechanism of combined therapy with KIF3C signaling pathway, afatinib, and MT-DC (ac)phosphoramide in regulating gastric cancer cell proliferation. Cell Signal 2024; 125:111514. [PMID: 39580063 DOI: 10.1016/j.cellsig.2024.111514] [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: 09/24/2024] [Revised: 11/11/2024] [Accepted: 11/15/2024] [Indexed: 11/25/2024]
Abstract
BACKGROUND KIF3C serves as a motor protein that facilitates axonal transport in neuronal cells. It belongs to the kinesin superfamily and plays a crucial role in the development of various cancers. However, the role of KIF3C in gastric cancer (GC) the third-highest cause of cancer-related deaths remains unclear. To investigate the regulatory mechanisms and expression patterns of KIF3C in GC and their implications for GC progression, we conducted a series of in vitro and in vivo experiments. METHODS We employed bioinformatics tools, including GEPIA, Kaplan-Meier plotter, and cBioPortal, to examine the role of KIF3C in GC, with a focus on its prognostic significance and associated signaling pathways. Furthermore, we conducted immunohistochemistry, real-time polymerase chain reaction (RT-PCR), western blot analyses, cell function and signaling pathway experiments. We further assessed the impact of combination therapy with afatinib and MT-DC (ac) phosphoramidite alongside KIF3C knockdown and overexpression in GC cells and a xenograft mouse model experiment. RESULTS Kaplan-Meier and Cox regression analyses revealed that high KIF3C expression in GC is significantly associated with poor prognosis. Genomic alteration and immune microenvironment analyses provided insights into the underlying causes of abnormal KIF3C expression. We observed that KIF3C knockdown decreased the proliferation of GC tumor cells. Additionally, KIF3C was overexpressed in GC and elevated expression was significantly correlated with tumor prognosis. We demonstrated that KIF3C knockdown and overexpression could significantly inhibit and promote tumor cell proliferation, respectively, through the combination therapy by modulating PI3K, AKT, and cell cycle signaling pathways. Notably, tumor size and the number of GC nodules were significantly reduced in the Sh-KIF3C group compared to the Sh-ctrl group. CONCLUSION Our findings highlight the potential of KIF3C as a biomarker for tumor progression diagnosis, establishing it as a pivotal therapeutic target for combating tumor advancement in GC.
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Affiliation(s)
- Maladho Tanta Diallo
- Northern Jiangsu People's Hospital, Yangzhou 225001, China; Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou 225001, China; General Surgery Institute of Yangzhou, Yangzhou University, Yangzhou 225001, China; Yangzhou Key Laboratory of Basic and Clinical Transformation of Digestive and Metabolic Diseases, Yangzhou, 225001, China
| | - Bangquan Chen
- Northern Jiangsu People's Hospital, Yangzhou 225001, China; Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou 225001, China; General Surgery Institute of Yangzhou, Yangzhou University, Yangzhou 225001, China; Yangzhou Key Laboratory of Basic and Clinical Transformation of Digestive and Metabolic Diseases, Yangzhou, 225001, China
| | - Zhang Yan
- Northern Jiangsu People's Hospital, Yangzhou 225001, China; Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou 225001, China; General Surgery Institute of Yangzhou, Yangzhou University, Yangzhou 225001, China
| | - Qiannan Sun
- Northern Jiangsu People's Hospital, Yangzhou 225001, China; Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou 225001, China; General Surgery Institute of Yangzhou, Yangzhou University, Yangzhou 225001, China; Yangzhou Key Laboratory of Basic and Clinical Transformation of Digestive and Metabolic Diseases, Yangzhou, 225001, China
| | - Guanghao Liu
- Northern Jiangsu People's Hospital, Yangzhou 225001, China; Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou 225001, China; General Surgery Institute of Yangzhou, Yangzhou University, Yangzhou 225001, China; Yangzhou Key Laboratory of Basic and Clinical Transformation of Digestive and Metabolic Diseases, Yangzhou, 225001, China
| | - Yong Wang
- Northern Jiangsu People's Hospital, Yangzhou 225001, China; Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou 225001, China; General Surgery Institute of Yangzhou, Yangzhou University, Yangzhou 225001, China; Yangzhou Key Laboratory of Basic and Clinical Transformation of Digestive and Metabolic Diseases, Yangzhou, 225001, China
| | - Jun Ren
- Northern Jiangsu People's Hospital, Yangzhou 225001, China; Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou 225001, China; General Surgery Institute of Yangzhou, Yangzhou University, Yangzhou 225001, China; Yangzhou Key Laboratory of Basic and Clinical Transformation of Digestive and Metabolic Diseases, Yangzhou, 225001, China.
| | - Daorong Wang
- Northern Jiangsu People's Hospital, Yangzhou 225001, China; Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou 225001, China; General Surgery Institute of Yangzhou, Yangzhou University, Yangzhou 225001, China; Yangzhou Key Laboratory of Basic and Clinical Transformation of Digestive and Metabolic Diseases, Yangzhou, 225001, China.
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Wang T, Zhang Q, Wang N, Liu Z, Zhang B, Zhao Y. Research Progresses of Targeted Therapy and Immunotherapy for Hepatocellular Carcinoma. Curr Med Chem 2021; 28:3107-3146. [PMID: 33050856 DOI: 10.2174/0929867327666201013162144] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 08/25/2020] [Accepted: 09/01/2020] [Indexed: 12/24/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide, with nearly one million new cases and deaths every year. Owing to the complex pathogenesis, hidden early symptoms, rapidly developing processes, and poor prognosis, the morbidity and mortality of HCC are increasing yearly. With the progress being made in modern medicine, the treatment of HCC is no longer limited to traditional methods. Targeted therapy and immunotherapy have emerged to treat advanced and metastatic HCC in recent years. Since Sorafenib is the first molecular targeting drug against angiogenesis, targeted drugs for HCC are continually emerging. Moreover, immunotherapy plays a vital role in clinical trials. In particular, the application of immune checkpoint inhibitors, which have received increasing attention in the field of cancer treatment, is a possible research path. Interestingly, these two therapies generally complement each other at some stages of HCC, bringing new hope for patients with advanced HCC. In this paper, we discuss the research progress of targeted therapy and immunotherapy for HCC in recent years, which will provide a reference for the further development of drugs for HCC.
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Affiliation(s)
- Tao Wang
- Institute of Drug Discovery Technology, Ningbo University, Ningbo, Zhejiang 315211, China
| | - Qiting Zhang
- Institute of Drug Discovery Technology, Ningbo University, Ningbo, Zhejiang 315211, China
| | - Ning Wang
- Institute of Drug Discovery Technology, Ningbo University, Ningbo, Zhejiang 315211, China
| | - Ziqi Liu
- Department of Pharmacy, the PLA Rocket Force Characteristic Medical Center, Beijing 100088, China
| | - Bin Zhang
- Li Dak Sum Yip Yio Chin Kenneth Li Marine Biopharmaceutical Research Center, Department of Marine Pharmacy, College of Food and Pharmaceutical Sciences, Ningbo University, Ningbo, Zhejiang 315211, China
| | - Yufen Zhao
- Institute of Drug Discovery Technology, Ningbo University, Ningbo, Zhejiang 315211, China
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3
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Koban R, Neumann M, Nelson PP, Ellerbrok H. Differential Efficacy of Novel Antiviral Substances in 3D and Monolayer Cell Culture. Viruses 2020; 12:v12111294. [PMID: 33198108 PMCID: PMC7697553 DOI: 10.3390/v12111294] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 11/04/2020] [Accepted: 11/10/2020] [Indexed: 12/18/2022] Open
Abstract
Repurposing of approved drugs that target host functions also important for virus replication promises to overcome the shortage of antiviral therapeutics. Mostly, virus biology including initial screening of antivirals is studied in conventional monolayer cells. The biology of these cells differs considerably from infected tissues. 3D culture models with characteristics of human tissues may reflect more realistically the in vivo events during infection. We screened first, second, and third generation epidermal growth factor receptor (EGFR)-inhibitors with different modes of action and the EGFR-blocking monoclonal antibody cetuximab in a 3D cell culture infection model with primary human keratinocytes and cowpox virus (CPXV) for antiviral activity. Antiviral activity of erlotinib and osimertinib was nearly unaffected by the cultivation method similar to the virus-directed antivirals tecovirimat and cidofovir. In contrast, the host-directed inhibitors afatinib and cetuximab were approx. 100-fold more efficient against CPXV in the 3D infection model, similar to previous results with gefitinib. In summary, inhibition of EGFR-signaling downregulates virus replication comparable to established virus-directed antivirals. However, in contrast to virus-directed inhibitors, in vitro efficacy of host-directed antivirals might be seriously affected by cell cultivation. Results obtained for afatinib and cetuximab suggest that screening of such drugs in standard monolayer culture might underestimate their potential as antivirals.
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Affiliation(s)
- Robert Koban
- Highly Pathogenic Viruses, Centre for Biological Threats and Special Pathogens, Robert Koch Institute, Seestr. 10, 13353 Berlin, Germany; (R.K.); (M.N.); (P.P.N.)
| | - Markus Neumann
- Highly Pathogenic Viruses, Centre for Biological Threats and Special Pathogens, Robert Koch Institute, Seestr. 10, 13353 Berlin, Germany; (R.K.); (M.N.); (P.P.N.)
| | - Philipp P. Nelson
- Highly Pathogenic Viruses, Centre for Biological Threats and Special Pathogens, Robert Koch Institute, Seestr. 10, 13353 Berlin, Germany; (R.K.); (M.N.); (P.P.N.)
| | - Heinz Ellerbrok
- Highly Pathogenic Viruses, Centre for Biological Threats and Special Pathogens, Robert Koch Institute, Seestr. 10, 13353 Berlin, Germany; (R.K.); (M.N.); (P.P.N.)
- Public Health Laboratory Support, Centre for International Health Protection, Nordufer 20, 13353 Berlin, Germany
- Correspondence: ; Tel.: +49-30-18754-2258
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Tripathi SK, Pandey K, Rengasamy KRR, Biswal BK. Recent updates on the resistance mechanisms to epidermal growth factor receptor tyrosine kinase inhibitors and resistance reversion strategies in lung cancer. Med Res Rev 2020; 40:2132-2176. [PMID: 32596830 DOI: 10.1002/med.21700] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Revised: 05/21/2020] [Accepted: 06/09/2020] [Indexed: 12/17/2022]
Abstract
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have led to a substantial improvement in the prognosis of lung cancer patients by explicitly targeting the activating mutations within the EGFR. Initially, patients harboring tumors with EGFR mutations show progression-free survival and improvement in the response rates toward all-generation EGFR-TKIs; however, these agents fail to deliver the intended results in the long-term due to drug resistance. Therefore, it is necessary to recognize specific cardinal mechanisms that regulate the resistance phenomenon. Understanding the intricate mechanisms underlying EGFR-TKIs resistance in lung cancer could provide cognizance for more advanced targeted therapeutics. The present review features insights into current updates on the discrete mechanisms, including secondary or tertiary mutations, parallel and downstream signaling pathways, acquiring an epithelial-to-mesenchymal transition (EMT) signature, microRNAs (miRNAs), and epigenetic alterations, which lead to intrinsic and acquired resistance against EGFR-TKIs in lung cancer. In addition, this paper also reviews current possible strategies to overcome this issue using combination treatment of recently developed MET inhibitors, allosteric inhibitors or immunotherapies, transformation of EMT, targeting miRNAs, and epigenetic alterations in intrinsic and acquired EGFR-TKIs resistant lung cancer. In conclusion, multiple factors are responsible for intrinsic and acquired resistance to EGFR-TKIs and understanding of the detailed molecular mechanisms, and recent advancements in pharmacological studies are needed to develop new strategies to overcome intrinsic and acquired EGFR-TKIs resistance in lung cancer.
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Affiliation(s)
- Surya K Tripathi
- Cancer Drug Resistance Laboratory, Department of Life Science, National Institute of Technology Rourkela, Rourkela, India
| | - Kamal Pandey
- Cancer Drug Resistance Laboratory, Department of Life Science, National Institute of Technology Rourkela, Rourkela, India
| | - Kannan R R Rengasamy
- Department of Bioresources and Food Science, Konkuk University, Seoul, South Korea
| | - Bijesh K Biswal
- Cancer Drug Resistance Laboratory, Department of Life Science, National Institute of Technology Rourkela, Rourkela, India
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Abstract
The Epidermal Growth Factor Receptor (EGFR) is frequently expressed at elevated levels in different forms of cancer and expression often correlates positively with cancer progression and poor prognosis. Different mutant forms of this protein also contribute to cancer heterogeneity. A constitutively active form of EGFR, EGFRvIII is one of the most important variants. EGFR is responsible for the maintenance and functions of cancer stem cells (CSCs), including stemness, metabolism, immunomodulatory-activity, dormancy and therapy-resistance. EGFR regulates these pathways through several signaling cascades, and often cooperates with other RTKs to exert further control. Inhibitors of EGFR have been extensively studied and display some anticancer efficacy. However, CSCs can also acquire resistance to EGFR inhibitors making effective therapy even more difficult. To ameliorate this limitation of EGFR inhibitors when used as single agents, it may be of value to simultaneously combine multiple EGFR inhibitors or use EGFR inhibitors with regulators of other important cancer phenotype regulating molecules, such as STAT3, or involved in important processes such as DNA repair. These combinatorial approaches require further experimental confirmation, but if successful would expand and improve therapeutic outcomes employing EGFR inhibitors as one arm of the therapy.
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6
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Shah R, Lester JF. Tyrosine Kinase Inhibitors for the Treatment of EGFR Mutation-Positive Non-Small-Cell Lung Cancer: A Clash of the Generations. Clin Lung Cancer 2019; 21:e216-e228. [PMID: 32014348 DOI: 10.1016/j.cllc.2019.12.003] [Citation(s) in RCA: 93] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 11/20/2019] [Accepted: 12/13/2019] [Indexed: 02/06/2023]
Abstract
The availability of 3 generations of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) with different pharmacologic characteristics and clinical profiles has provided oncologists with a potentially confusing choice for the treatment of EGFR mutation-positive non-small-cell lung cancer. Although recent head-to-head clinical trials have demonstrated improved efficacy with second-generation (ie, afatinib, dacomitinib) and third-generation (ie, osimertinib) TKIs compared with the first-generation TKIs (eg, erlotinib, gefitinib), acquired resistance has been inevitable, regardless of which agent has been chosen as first-line therapy. Thus, the potential availability of subsequent treatment options is an important consideration. Recent data have demonstrated that osimertinib confers an overall survival benefit compared with first-generation EGFR TKIs, and dacomitinib has shown an overall survival benefit compared with gefitinib in an exploratory analysis. However, the relative benefits of different sequential EGFR-TKI regimens, especially those involving second- and third-generation agents, have remained uncertain and require prospective evaluation. Few such data currently exist to inform treatment choices. In the present review, we examined the pharmacologic characteristics and current clinical data for EGFR TKIs, including emerging information on the molecular mechanisms of resistance across the different generations of TKIs. Given the uncertainties regarding the optimal treatment choice, we have focused on the factors that might help determine the treatment decisions, such as efficacy and safety in patient subgroups. We also discussed the emerging real-world data, which have provided some insights into the benefits of sequential regimens in everyday clinical practice.
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Affiliation(s)
- Riyaz Shah
- Kent Oncology Centre, Maidstone Hospital, Kent, UK.
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Overexpression of miR-758 inhibited proliferation, migration, invasion, and promoted apoptosis of non-small cell lung cancer cells by negatively regulating HMGB. Biosci Rep 2019; 39:BSR20180855. [PMID: 30446524 PMCID: PMC6340954 DOI: 10.1042/bsr20180855] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Revised: 11/04/2018] [Accepted: 11/15/2018] [Indexed: 12/20/2022] Open
Abstract
Non-small cell lung cancer (NSCLC) is one of the most fatal types of cancer with significant mortality and morbidity worldwide. MicroRNAs (miRs) have been confirmed to have positive functions in NSCLC. In the present study, we try to explore the role of miR-758 in proliferation, migration, invasion, and apoptosis of NSCLC cells by regulating high-mobility group box (HMGB) 3 (HMGB3.) NSCLC and adjacent tissues were collected. Reverse transcription quantitative PCR (RT-qPCR) was employed to detect expression of miR-758 and HMGB3 in NSCLC and adjacent tissues, in BEAS-2B cells and NSCLC cell lines. The targetted relationship between miR-758 and HMGB3 was identified by dual luciferase reporter gene assay. The effects of miR-758 on proliferation, migration, invasion, cell cycle, and apoptosis of A549 cells. MiR-758 expression was lower in NSCLC tissues, which was opposite to HMGB3 expression. The results also demonstrated that miR-758 can target HMGB3. The cells transfected with miR-758 mimic had decreased HMGB3 expression, proliferation, migration, and invasion, with more arrested cells in G1 phase and increased apoptosis. Our results supported that the overexpression of miR-758 inhibits proliferation, migration, and invasion, and promotes apoptosis of NSCLC cells by negative regulating HMGB2. The present study may provide a novel target for NSCLC treatment.
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8
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Abstract
The last 100 years have seen a dramatic alteration in the treatment of cancer. Aside from small molecule inhibitors of protein tyrosine kinases, monoclonal antibodies have also been found to provide valuable therapeutic approaches for modulating tumour pathophysiology. As our knowledge of cancer biology improves, the specificity of this new generation of drugs is generally delivering an improved therapeutic ratio compared to traditional cytotoxic agents. However, patient selection through the use of biomarkers is key in optimising efficacy and improving cost-effectiveness. The most recent wave of revolutionary new systemic therapy approaches to cancer has arrived in recent years in the form of immune checkpoint inhibitors, now clinically validated as modulators of immune-regulatory pathways. The future of oncology therapeutics includes a combination of cytotoxic agents, targeted therapies and immunotherapy.
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Affiliation(s)
| | - James Spicer
- King's Health Partners at Guy's Hospital, London, UK.
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9
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Kohsaka S, Petronczki M, Solca F, Maemondo M. Tumor clonality and resistance mechanisms in EGFR mutation-positive non-small-cell lung cancer: implications for therapeutic sequencing. Future Oncol 2018; 15:637-652. [PMID: 30404555 DOI: 10.2217/fon-2018-0736] [Citation(s) in RCA: 78] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
While the development of EGFR-targeted tyrosine kinase inhibitors (TKIs) has revolutionized treatment of EGFR mutation-positive non-small-cell lung cancer, acquired resistance to therapy is inevitable, reflecting tumor evolution. Recent studies show that EGFR mutation-positive non-small-cell lung cancer is highly heterogeneous at the cellular level, facilitating clonal expansion of resistant tumors via multiple molecular mechanisms. Here, we review the mechanistic differences between first-, second- and third-generation EGFR-targeted TKIs and speculate how these features could explain differences in clinical activity between these agents from a clonal evolution perspective. We hypothesize that the molecular dissection of tumor resistance mechanisms will facilitate optimal sequential use of EGFR TKIs in individual patients, thus maximizing the duration of chemotherapy-free treatment and survival benefit.
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Affiliation(s)
- Shinji Kohsaka
- Division of Cellular Signaling, National Cancer Center Research Institute, Tokyo, Japan
| | | | - Flavio Solca
- Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
| | - Makoto Maemondo
- Department of Internal Medicine, Iwate Medical University, Morioka, Japan
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Wang N, Zhang T. Downregulation of MicroRNA-135 Promotes Sensitivity of Non-Small Cell Lung Cancer to Gefitinib by Targeting TRIM16. Oncol Res 2018; 26:1005-1014. [PMID: 29295721 PMCID: PMC7844745 DOI: 10.3727/096504017x15144755633680] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Personalized treatment targeting the epidermal growth factor receptor (EGFR) may be a promising new treatment of non-small cell lung cancer (NSCLC). Gefitinib, a tyrosine kinase inhibitor, is the first drug for NSCLC, which unfortunately easily leads to drug resistance. Our study aimed to explore the functional role of microRNA (miR)-135 in the sensitivity to gefitinib of NSCLC cells. Expression of miR-135 in normal cells and NSCLC cells was assessed, followed by the effects of abnormally expressed miR-135 on cell viability, migration, invasion, apoptosis, sensitivity to gefitinib, and the expression levels of adhesion molecules and programmed death ligand 1 (PD-L1) in H1650 and H1975 cells. Next, the possible target gene of miR-135 was screened and verified. Finally, the potential involvement of the JAK/STAT signaling pathway was investigated. Expression of miR-135 was upregulated in NSCLC cells, and miR-135 silencing repressed cell viability, migration, and invasion, but increased cell apoptosis and sensitivity to gefitinib. E-cadherin and β-catenin were significantly upregulated, but PD-L1 was downregulated by the silencing of miR-135. Subsequently, tripartite-motif (TRIM) 16 was screened and verified to be a target gene of miR-135, and miR-135 suppression was shown to function through upregulation of TRIM16 expression. Phosphorylated levels of the key kinases in the JAK/STAT pathway were reduced by silencing miR-135 by targeting TRIM16. In conclusion, miR-135 acted as a tumor promoter, and its suppression could improve sensitivity to gefitinib by targeting TRIM16 and inhibition of the JAK/STAT pathway.
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Affiliation(s)
- Ning Wang
- *Department of Thoracic Surgery, Shengli Oilfield Central Hospital, Dongying, P.R. China
| | - Tingting Zhang
- †Department of Oncology, Shengli Oilfield Central Hospital, Dongying, P.R. China
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Izzedine H, Perazella MA. Adverse kidney effects of epidermal growth factor receptor inhibitors. Nephrol Dial Transplant 2018; 32:1089-1097. [PMID: 28339780 DOI: 10.1093/ndt/gfw467] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2016] [Accepted: 12/15/2016] [Indexed: 12/17/2022] Open
Abstract
The epidermal growth factor receptor (EGFR) is implicated in various malignancies. The past decade has seen the development and widespread use of EGFR inhibitors for the successful treatment of such cancers. Available EGFR inhibitors include small molecule tyrosine-kinase inhibitors and monoclonal antibodies. Class-related renal adverse events result in dual toxicity including tubular/electrolyte disorders and glomerulopathies. Tubular injury is common and mainly due to monoclonal antibodies while glomerulopathy is rare and related to various anti-EGFR agents. The exact pathogenesis of anti-EGFR agents associated with kidney disorders remains to be elucidated.
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Affiliation(s)
- Hassan Izzedine
- Department of Nephrology, Monceau Park International Clinic, Paris, France
| | - Mark A Perazella
- Department of Nephrology, Yale University School of Medicine, New Haven, CT, USA
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12
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Arrieta O, Cruz-Rico G, Soto-Perez-de-Celis E, Ramírez-Tirado LA, Caballe-Perez E, Martínez-Hernández JN, Martinez-Alvarez I, Soca-Chafre G, Macedo-Pérez EO, Astudillo-de la Vega H. Reduction in Hepatocyte Growth Factor Serum Levels is Associated with Improved Prognosis in Advanced Lung Adenocarcinoma Patients Treated with Afatinib: a Phase II Trial. Target Oncol 2017; 11:619-629. [PMID: 27033062 DOI: 10.1007/s11523-016-0425-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND C-met and its ligand, hepatocyte growth factor (HGF) have been associated with the resistance mechanism of EGFR-TKIs. HGF was evaluated as a clinical-marker of response in NSCLC patients treated with afatinib. METHODS Sixty-six patients with stage IIIB/IV lung adenocarcinoma and progression to any-line chemotherapy received afatinib 40 mg/day. Mutational EGFR and HER2 status were assessed by RT-PCR. HER2 amplification was evaluated by FISH. Serum HGF content was measured by ELISA before and 2 months after the start of treatment. HGF levels were assessed with the objective response rate (ORR), progression-free-survival (PFS), and overall survival (OS). This trial was registered on ClinicalTrials.gov: NCT01542437. RESULTS Fifty patients (75 %) were EGFR mutation positive. Response was achieved in 59 % of all patients and 78 % of EGFR mutated patients. Median PFS was 10 [95 % CI 6.8-13.1] and 14.5 months [10.9-18.9] for all and EGFR mutated patients, respectively. Median OS was 22.8 [17.5-28.1] and 32.4 months [18.3-46.6] for all and EGFR mutated patients, respectively. Patients with reduced serum HGF levels had improved ORR (75 % vs 44 %; p = 0.011), PFS (15.1 [2.9-27.3] vs 6.5 months [3.9-9.1]; p = 0.005) and OS (NR vs 14.5 months [7.8 - 21.3] p = 0.007). A reduction in serum HGF levels was an independent factor associated with longer PFS (HR 0.40; p = 0.021) and OS (HR 0.31; p = 0.006) in all and EGFR mutated patients. CONCLUSIONS A reduction in serum HGF levels was associated with improved outcomes in patients treated with afatinib. These results suggest HGF might have a role as a mechanism of resistance to EGFR-TKIs. HGF could represent a potential therapeutic target to prevent or reverse resistance particularly in EGFR mutated patients.
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Affiliation(s)
- Oscar Arrieta
- Thoracic Oncology Unit, Instituto Nacional de Cancerología de México (INCan), Av. San Fernando No. 22, Col. Sección XVI, Tlalpan, CP 14080, Mexico City, Mexico.
- Experimental Oncology Laboratory, INCan, Av. San Fernando No. 22, Col. Sección XVI, Delegación Tlalpan, CP 14080, Mexico City, Mexico.
| | - Graciela Cruz-Rico
- Experimental Oncology Laboratory, INCan, Av. San Fernando No. 22, Col. Sección XVI, Delegación Tlalpan, CP 14080, Mexico City, Mexico
| | - Enrique Soto-Perez-de-Celis
- Cancer Care in the Elderly Clinic, Department of Geriatrics, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Av. Vasco de Quiroga No. 15, Col. Sección XVI, Tlalpan, CP 14080, Mexico City, Mexico
| | - Laura-Alejandra Ramírez-Tirado
- Experimental Oncology Laboratory, INCan, Av. San Fernando No. 22, Col. Sección XVI, Delegación Tlalpan, CP 14080, Mexico City, Mexico
| | - Enrique Caballe-Perez
- Thoracic Oncology Unit, Instituto Nacional de Cancerología de México (INCan), Av. San Fernando No. 22, Col. Sección XVI, Tlalpan, CP 14080, Mexico City, Mexico
| | - Jorge-Negueb Martínez-Hernández
- Thoracic Oncology Unit, Instituto Nacional de Cancerología de México (INCan), Av. San Fernando No. 22, Col. Sección XVI, Tlalpan, CP 14080, Mexico City, Mexico
| | - Ivan Martinez-Alvarez
- Thoracic Oncology Unit, Instituto Nacional de Cancerología de México (INCan), Av. San Fernando No. 22, Col. Sección XVI, Tlalpan, CP 14080, Mexico City, Mexico
| | - Giovanny Soca-Chafre
- Experimental Oncology Laboratory, INCan, Av. San Fernando No. 22, Col. Sección XVI, Delegación Tlalpan, CP 14080, Mexico City, Mexico
| | - Eleazar Omar Macedo-Pérez
- Thoracic Oncology Unit, Instituto Nacional de Cancerología de México (INCan), Av. San Fernando No. 22, Col. Sección XVI, Tlalpan, CP 14080, Mexico City, Mexico
| | - Horacio Astudillo-de la Vega
- Laboratory of Translational Cancer Research and Cellular Therapy, Oncology Hospital, Medical Center Siglo XXI, Mexican Institute of Social Security (IMSS), CP 06720, Mexico City, Mexico
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Bohn JP, Pall G, Stockhammer G, Steurer M. Targeted Therapies for the Treatment of Brain Metastases in Solid Tumors. Target Oncol 2017; 11:263-75. [PMID: 26822319 DOI: 10.1007/s11523-015-0414-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Brain metastases are a major cause of morbidity and mortality in cancer patients. While the mainstay treatment comprises surgery and radiation therapy, the role of systemic agents remains controversial. In general, it has been presumed that poor blood-brain barrier (BBB) penetration and inherently more resistant metastatic brain disease preclude a favorable systemic treatment approach. However, a better understanding of tumor biology and the subsequent development of targeted drugs have reawakened interest in systemic therapy. Despite still limited brain distribution, a variety of targeted drugs have demonstrated activity in brain metastases in early clinical trials. Nevertheless, disease progression commonly occurs, and it remains to be elucidated whether limited CNS drug distribution or the acquisition of resistant metastatic clones must be held responsible for this prognosis. Moreover, micrometastatic brain disease beyond an intact BBB-and ultimately prevention of brain metastasis formation-may generally remain inaccessible for first-generation targeted agents with poor CNS penetration. To overcome limited brain distribution and possibly emerging acquired resistance, highly potent next-generation targeted drugs with enhanced CNS distribution have been developed. In view of this emerging but yet undefined role of targeted therapies in the treatment of brain metastases from solid tumors, this review aims to summarize the current knowledge from clinical trials and discusses clinically relevant obstacles to overcome.
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Affiliation(s)
- Jan-Paul Bohn
- Department of Internal Medicine V, Medical University of Innsbruck, Anichstrasse 35, A-6020, Innsbruck, Austria.
| | - Georg Pall
- Department of Internal Medicine V, Medical University of Innsbruck, Anichstrasse 35, A-6020, Innsbruck, Austria
| | - Guenther Stockhammer
- Department of Neurology and Neurosurgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Michael Steurer
- Department of Internal Medicine V, Medical University of Innsbruck, Anichstrasse 35, A-6020, Innsbruck, Austria
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14
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Niessen S, Dix MM, Barbas S, Potter ZE, Lu S, Brodsky O, Planken S, Behenna D, Almaden C, Gajiwala KS, Ryan K, Ferre R, Lazear MR, Hayward MM, Kath JC, Cravatt BF. Proteome-wide Map of Targets of T790M-EGFR-Directed Covalent Inhibitors. Cell Chem Biol 2017; 24:1388-1400.e7. [PMID: 28965727 DOI: 10.1016/j.chembiol.2017.08.017] [Citation(s) in RCA: 65] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Revised: 06/30/2017] [Accepted: 08/17/2017] [Indexed: 12/30/2022]
Abstract
Patients with non-small cell lung cancers that have kinase-activating epidermal growth factor receptor (EGFR) mutations are highly responsive to first- and second-generation EGFR inhibitors. However, these patients often relapse due to a secondary, drug-resistant mutation in EGFR whereby the gatekeeper threonine is converted to methionine (T790M). Several third-generation EGFR inhibitors have been developed that irreversibly inactivate T790M-EGFR while sparing wild-type EGFR, thus reducing epithelium-based toxicities. Using chemical proteomics, we show here that individual T790M-EGFR inhibitors exhibit strikingly distinct off-target profiles in human cells. The FDA-approved drug osimertinib (AZD9291), in particular, was found to covalently modify cathepsins in cell and animal models, which correlated with lysosomal accumulation of the drug. Our findings thus show how chemical proteomics can be used to differentiate covalent kinase inhibitors based on global selectivity profiles in living systems and identify specific off-targets of these inhibitors that may affect drug activity and safety.
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Affiliation(s)
- Sherry Niessen
- Worldwide Medicinal Chemistry, La Jolla Laboratories, Pfizer Worldwide Research and Development, 10770 Science Center Drive, San Diego, CA 92121, USA; Oncology RU, La Jolla Laboratories, Pfizer Worldwide Research and Development, 10770 Science Center Drive, San Diego, CA 92121, USA.
| | - Melissa M Dix
- Department of Molecular Medicine, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA
| | - Sabrina Barbas
- Worldwide Medicinal Chemistry, La Jolla Laboratories, Pfizer Worldwide Research and Development, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - Zachary E Potter
- Department of Molecular Medicine, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA
| | - Shuyan Lu
- Drug Safety Research and Development, La Jolla Laboratories, Pfizer Worldwide Research and Development, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - Oleg Brodsky
- Worldwide Medicinal Chemistry, La Jolla Laboratories, Pfizer Worldwide Research and Development, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - Simon Planken
- Worldwide Medicinal Chemistry, La Jolla Laboratories, Pfizer Worldwide Research and Development, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - Douglas Behenna
- Worldwide Medicinal Chemistry, La Jolla Laboratories, Pfizer Worldwide Research and Development, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - Chau Almaden
- Oncology RU, La Jolla Laboratories, Pfizer Worldwide Research and Development, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - Ketan S Gajiwala
- Worldwide Medicinal Chemistry, La Jolla Laboratories, Pfizer Worldwide Research and Development, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - Kevin Ryan
- Worldwide Medicinal Chemistry, La Jolla Laboratories, Pfizer Worldwide Research and Development, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - RoseAnn Ferre
- Worldwide Medicinal Chemistry, La Jolla Laboratories, Pfizer Worldwide Research and Development, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - Michael R Lazear
- Department of Molecular Medicine, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA
| | - Matthew M Hayward
- Discovery Sciences, Pfizer Worldwide Research and Development, MS 8220-2226 Eastern Point Road, Groton, CT 06340, USA
| | - John C Kath
- Worldwide Medicinal Chemistry, La Jolla Laboratories, Pfizer Worldwide Research and Development, 10770 Science Center Drive, San Diego, CA 92121, USA
| | - Benjamin F Cravatt
- Department of Molecular Medicine, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.
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15
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Li X, Yang C, Wan H, Zhang G, Feng J, Zhang L, Chen X, Zhong D, Lou L, Tao W, Zhang L. Discovery and development of pyrotinib: A novel irreversible EGFR/HER2 dual tyrosine kinase inhibitor with favorable safety profiles for the treatment of breast cancer. Eur J Pharm Sci 2017; 110:51-61. [PMID: 28115222 DOI: 10.1016/j.ejps.2017.01.021] [Citation(s) in RCA: 164] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2016] [Revised: 12/13/2016] [Accepted: 01/19/2017] [Indexed: 02/06/2023]
Abstract
The discovery and development of a novel irreversible EGFR/HER2 dual tyrosine kinase inhibitor SHR1258 (pyrotinib) for the treatment of HER2-postive breast cancer is presented. The structure-activity relationship of lead series and their pharmacokinetic properties were evaluated to identify the potential candidates for further in vivo efficacy studies and preclinical safety assessments. Metabolic pathway and drug-drug interaction were also investigated in preclinical settings. In particular, major metabolites in human and animal species were assessed with regard to potential toxicity or off-target side effects. Overall, the potent and selective EGFR/HER2 dual inhibitor, pyrotinib, displayed robust anti-tumor effects on HER2-overexpressing xenograft models and sufficiently safety windows in animals as well as favorable pharmacokinetic properties in human, which substantially ensures current clinical development. Finally, recent advances of pyrotinib in clinical studies are highlighted with very encouraging outcomes in patients with HER2-postive advanced breast cancer.
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Affiliation(s)
- Xin Li
- Shanghai Hengrui Pharmaceutical Co., Ltd., 279 Wenjing Road, Shanghai 200245, China.
| | - Changyong Yang
- Jiangsu Hengrui Medicine Co., Ltd., Jiangsu, Lianyungang 222047, China.
| | - Hong Wan
- Shanghai Hengrui Pharmaceutical Co., Ltd., 279 Wenjing Road, Shanghai 200245, China.
| | - Ge Zhang
- Jiangsu Hengrui Medicine Co., Ltd., Jiangsu, Lianyungang 222047, China.
| | - Jun Feng
- Shanghai Hengrui Pharmaceutical Co., Ltd., 279 Wenjing Road, Shanghai 200245, China.
| | - Lei Zhang
- Shanghai Hengrui Pharmaceutical Co., Ltd., 279 Wenjing Road, Shanghai 200245, China.
| | - Xiaoyan Chen
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
| | - Dafang Zhong
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
| | - Liguang Lou
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
| | - Weikang Tao
- Shanghai Hengrui Pharmaceutical Co., Ltd., 279 Wenjing Road, Shanghai 200245, China.
| | - Lianshan Zhang
- Jiangsu Hengrui Medicine Co., Ltd., Jiangsu, Lianyungang 222047, China; China Pharmaceutical University, Jiangsu Key Laboratory of Drug Design and Optimization, Nanjing 210009, China.
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16
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Barron F, de la Torre-Vallejo M, Luna-Palencia RL, Cardona AF, Arrieta O. The safety of afatinib for the treatment of non-small cell lung cancer. Expert Opin Drug Saf 2016; 15:1563-1572. [PMID: 27633264 DOI: 10.1080/14740338.2016.1236910] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
INTRODUCTION Lung cancer tumors present EGFR mutations associated with an increased response rate to tyrosine kinase inhibitors (TKIs). Afatinib acts as an irreversible pan-ErbB-TKI. Areas covered: This review summarizes the results of clinical trials in NSCLC regarding its safety and efficacy. Expert opinion: Afatinib in 40 mg doses is highly effective in patients with NSCLC and EGFR mutations, improving progression-free survival and disease-related symptoms compared to chemotherapy. Additionally, afatinib has a better response rate and shows a small benefit in progression free survival compared to first-generation TKIs, and patients with exon 19 deletion could represent a subgroup with better prognosis and overall survival. Diarrhea, mucositis and rash are frequent adverse events induced by afatinib, these can impair quality of life and sometimes afatinib discontinuation is necessary. Management of adverse events, including early antidiarrheal treatment and prophylactic or early antibiotic management can reduce the gastrointestinal and cutaneous adverse events, respectively. Different risk factors, including malnourishment, sarcopenia, and low body surface might be associated with a higher toxicity risk, and these groups of patients could begin treatment with a low dose of afatinib followed by a close evaluation on tolerability and toxicity in order to slowly increase the dosage of afatinib.
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Affiliation(s)
- Feliciano Barron
- a Thoracic Oncology Unit , Instituto Nacional de Cancerología , Mexico City , Mexico
| | | | | | - Andres F Cardona
- b Clinical and Translational Oncology Group, Institute of Oncology , Clínica del Country , Bogota , Colombia
| | - Oscar Arrieta
- a Thoracic Oncology Unit , Instituto Nacional de Cancerología , Mexico City , Mexico
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17
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Passaro A, Pochesci A, Spitaleri G, Catania C, Noberasco C, Del Signore E, de Marinis F. Afatinib for the first-line treatment of patients with metastatic EGFR-positive NSCLC: a look at the data. Expert Rev Clin Pharmacol 2016; 9:1283-1288. [PMID: 27626838 DOI: 10.1080/17512433.2016.1233059] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
INTRODUCTION Epidermal growth factor receptor (EGFR) mutations are detected in about 10-15% of Caucasian and 30-40% of Asian patients with advanced or metastatic non-small-cell lung cancer (NSCLC). In patients harbouring EGFR mutations, the treatment with different available EGFR tyrosine kinase inhibitors (TKIs) showed to be more effective and safe than platinum-based chemotherapy regimens. Areas covered: The current evidences about the role of afatinib for patients with EGFR-positive NSCLC are reviewed and discussed. We report a review based on a MEDLINE/PubMed, searched for randomized phase II or III trials evaluating afatinib in EGFR-positive NSCLC. Expert commentary: Afatinib is the third EGFR TKI approved for the treatment of NSCLC harbouring EGFR mutations, showing high efficacy in this setting of patients.
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Affiliation(s)
- Antonio Passaro
- a Division of Thoracic Oncology , European Institute of Oncology , Milan , Italy
| | - Alessia Pochesci
- a Division of Thoracic Oncology , European Institute of Oncology , Milan , Italy
| | - Gianluca Spitaleri
- a Division of Thoracic Oncology , European Institute of Oncology , Milan , Italy
| | - Chiara Catania
- a Division of Thoracic Oncology , European Institute of Oncology , Milan , Italy
| | - Cristina Noberasco
- a Division of Thoracic Oncology , European Institute of Oncology , Milan , Italy
| | - Ester Del Signore
- a Division of Thoracic Oncology , European Institute of Oncology , Milan , Italy
| | - Filippo de Marinis
- a Division of Thoracic Oncology , European Institute of Oncology , Milan , Italy
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18
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Macedo JE. New era of epidermal growth factor receptor-tyrosine kinase inhibitors for lung cancer. World J Respirol 2016; 6:57-62. [DOI: 10.5320/wjr.v6.i2.57] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Accepted: 06/29/2016] [Indexed: 02/06/2023] Open
Abstract
Lung cancer is the leading cause of death globally, besides recent advances in its management; it maintains a low 5-year survival rate of 15%. The discovery of epidermal growth factor receptor (EGFR) activating mutations and the introduction of its tyrosine kinase inhibitors (TKIs) have expanded the treatment options for patients with non-small cell lung cancer. Nowadays, EGFR mutation testing is now a common routine for newly diagnosed lung cancer. First generation TKIs developed, erlotinib and gefitinib, were reversible ones. After a median of 14 mo, eventually all EGFR mutated patients develop resistance to reversible TKIs. Afatinib, dacomitinib and neratinib, second generation inhibitors, are selective and irreversible TKIs. Finally, third generation phase I clinical trials were performed, with lower toxicity profiles, and targeting with more precision the driving clone of this heterogeneous disease.
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19
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De Pauw I, Wouters A, Van den Bossche J, Peeters M, Pauwels P, Deschoolmeester V, Vermorken JB, Lardon F. Preclinical and clinical studies on afatinib in monotherapy and in combination regimens: Potential impact in colorectal cancer. Pharmacol Ther 2016; 166:71-83. [PMID: 27373506 DOI: 10.1016/j.pharmthera.2016.06.014] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/15/2016] [Indexed: 12/15/2022]
Abstract
Targeting the epidermal growth factor receptor (EGFR) with monoclonal antibodies (mAbs) or tyrosine kinase inhibitors (TKI) has been an interesting therapeutic strategy because aberrant activation of this receptor plays an important role in the tumorgenesis of many cancer types, including colorectal cancer (CRC). After the initial promising results of EGFR-targeted therapies, therapeutic resistance is a major clinical problem. In order to overcome resistance to these EGFR-targeted therapies, new treatment options are necessary. In contrast to first generation EGFR inhibitors, afatinib (BIBW2992) is a second-generation irreversible ErbB family blocker that inhibits EGFR as well as HER2 and HER4. Consequently, treatment with afatinib may result in a distinct and more pronounced therapeutic benefit. Preclinical studies have reported promising results for afatinib in monotherapy as well as in combination with other drugs in CRC model systems. Furthermore, clinical studies examining afatinib as single agent and in combination therapy demonstrated manageable safety profile. Nevertheless, only limited antitumor activity has been observed in CRC patients. Although several combination treatments with afatinib have already been investigated, no optimal combination has been identified for CRC patients yet. As molecular tumor characteristics have gained increased importance in the choice of treatment, additional studies with biomarker-driven patient recruitment are required to further explore afatinib efficacy in CRC.
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Affiliation(s)
- I De Pauw
- Center for Oncological Research (CORE), University of Antwerp, Belgium.
| | - A Wouters
- Center for Oncological Research (CORE), University of Antwerp, Belgium
| | - J Van den Bossche
- Center for Oncological Research (CORE), University of Antwerp, Belgium
| | - M Peeters
- Center for Oncological Research (CORE), University of Antwerp, Belgium; Department of Oncology, Antwerp University Hospital, Belgium
| | - P Pauwels
- Center for Oncological Research (CORE), University of Antwerp, Belgium; Department of Pathology, Antwerp University Hospital, Belgium
| | - V Deschoolmeester
- Center for Oncological Research (CORE), University of Antwerp, Belgium; Department of Pathology, Antwerp University Hospital, Belgium
| | - J B Vermorken
- Center for Oncological Research (CORE), University of Antwerp, Belgium; Department of Oncology, Antwerp University Hospital, Belgium
| | - F Lardon
- Center for Oncological Research (CORE), University of Antwerp, Belgium
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20
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Wang Y, Guo Z, Li Y, Zhou Q. Development of epidermal growth factor receptor tyrosine kinase inhibitors against EGFR T790M. Mutation in non small-cell lung carcinoma. Open Med (Wars) 2016; 11:68-77. [PMID: 28352770 PMCID: PMC5329801 DOI: 10.1515/med-2016-0014] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2015] [Accepted: 02/25/2016] [Indexed: 11/15/2022] Open
Abstract
Individualized therapies targeting epidermal growth factor receptor (EGFR) mutations show promises for the treatment of non small-cell lung carcinoma (NSCLC). However, disease progression almost invariably occurs 1 year after tyrosine kinase inhibitor (TKI) treatment. The most prominent mechanism of acquired resistance involves the secondary EGFR mutation, namely EGFR T790M, which accounts for 50%-60% of resistant tumors. A large amount of studies have focused on the development of effective strategies to treat TKI-resistant EGFR T790M mutation in lung tumors. Novel generations of EGFR inhibitors are producing encouraging results in patients with acquired resistance against EGFR T790M mutation. This review will summarize the novel inhibitors, which might overcome resistance against EGFR T790M mutation.
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Affiliation(s)
- Yuli Wang
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Zhitao Guo
- Orthopedics Sector 1, Tianjin Xiqing hospital, Tianjin, 300380, China
| | - Yang Li
- Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Qinghua Zhou
- 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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21
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Kool MMJ, Galac S, van der Helm N, Corradini S, Kooistra HS, Mol JA. Insulin-like growth factor--phosphatidylinositol 3 kinase signaling in canine cortisol-secreting adrenocortical tumors. J Vet Intern Med 2015; 29:214-24. [PMID: 25619516 PMCID: PMC4858057 DOI: 10.1111/jvim.12528] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Revised: 11/19/2014] [Accepted: 11/19/2014] [Indexed: 01/06/2023] Open
Abstract
Background Hypercortisolism is a common endocrine disorder in dogs, caused by a cortisol‐secreting adrenocortical tumor (AT) in approximately 15% of cases. In adrenocortical carcinomas of humans, activation of the phosphatidylinositol 3 kinase (PI3K) signaling pathway by insulin‐like growth factor (IGF) signaling represents a promising therapeutic target. Objectives To investigate the involvement of PI3K signaling in the pathogenesis of ATs in dogs and to identify pathway components that may hold promise as future therapeutic targets or as prognostic markers. Animals Analyses were performed on 36 canine cortisol‐secreting ATs (11 adenomas and 25 carcinomas) and 15 normal adrenal glands of dogs. Methods mRNA expression analysis was performed for PI3K target genes, PI3K inhibitor phosphatase and tensin homolog (PTEN), IGFs, IGF receptors, IGF binding proteins and epidermal growth factor receptors. Mutation analysis was performed on genes encoding PTEN and PI3K catalytic subunit (PIK3CA). Results Target gene expression indicated PI3K activation in carcinomas, but not in adenomas. No amino acid‐changing mutations were detected in PTEN or PIK3CA and no significant alterations in IGF‐II or IGFR1 expression were detected. In carcinomas, ERBB2 expression tended to be higher than in normal adrenal glands, and higher expression of inhibitor of differentiation 1 and 2 (ID1 and ID2) was detected in carcinomas with recurrence within 2.5 years after adrenalectomy. Conclusions and Clinical Importance Based on these results, ERBB2 might be a promising therapeutic target in ATs in dogs, whereas ID1 and 2 might be valuable as prognostic markers and therapeutic targets.
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Affiliation(s)
- M M J Kool
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
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22
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Giordano P, Manzo A, Montanino A, Costanzo R, Sandomenico C, Piccirillo MC, Daniele G, Normanno N, Carillio G, Rocco G, Bianco R, Perrone F, Morabito A. Afatinib: An overview of its clinical development in non-small-cell lung cancer and other tumors. Crit Rev Oncol Hematol 2015; 97:143-51. [PMID: 26318094 DOI: 10.1016/j.critrevonc.2015.08.016] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2015] [Revised: 07/08/2015] [Accepted: 08/06/2015] [Indexed: 12/11/2022] Open
Abstract
Afatinib is an oral, irreversible, tyrosine kinase inhibitor (TKI) of EGFR, HER2 and HER4. According to phase I studies, the recommended dose of afatinib was 50mg daily. Rash, acne, diarrhea and stomatitis were the most common adverse events. Afatinib failed to demonstrate an improvement in overall survival in unselected heavily pretreated NSCLC patients (Lux-Lung-1). On the contrary, the Lux-Lung-3 and -6 trials met the primary end point, demonstrating a significant increase in terms of PFS with afatinib compared with chemotherapy in the first line treatment of EGFR mutant patients. Moreover, in both studies, afatinib improved overall survival in patients with exon 19 EGFR deletion (31.7 vs 20.7 months; HR: 0.59, p=0.0001). The results of ongoing randomized trials should further clarify the efficacy of afatinib compared with first-generation TKIs in advanced NSCLC, its activity in the adjuvant and neoadjuvant settings, as well as its efficacy in other tumors.
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Affiliation(s)
- Pasqualina Giordano
- Medical Oncology Unit, Thoracic Department, Istituto Nazionale Tumori, "Fondazione G. Pascale" - IRCCS, Napoli, Italy; Clinical Trials Unit, Istituto Nazionale Tumori, "Fondazione G.Pascale" - IRCCS, Napoli, Italy
| | - Anna Manzo
- Medical Oncology Unit, Thoracic Department, Istituto Nazionale Tumori, "Fondazione G. Pascale" - IRCCS, Napoli, Italy
| | - Agnese Montanino
- Medical Oncology Unit, Thoracic Department, Istituto Nazionale Tumori, "Fondazione G. Pascale" - IRCCS, Napoli, Italy
| | - Raffaele Costanzo
- Medical Oncology Unit, Thoracic Department, Istituto Nazionale Tumori, "Fondazione G. Pascale" - IRCCS, Napoli, Italy
| | - Claudia Sandomenico
- Medical Oncology Unit, Thoracic Department, Istituto Nazionale Tumori, "Fondazione G. Pascale" - IRCCS, Napoli, Italy
| | | | - Gennaro Daniele
- Clinical Trials Unit, Istituto Nazionale Tumori, "Fondazione G.Pascale" - IRCCS, Napoli, Italy
| | - Nicola Normanno
- Cellular Biology and Biotherapy, Istituto Nazionale Tumori, "Fondazione G.Pascale" - IRCCS, Napoli, Italy; Centro di Ricerche Oncologiche di Mercogliano (CROM), Mercogliano, Avellino, Italy
| | - Guido Carillio
- Department of Oncology and Hematology, Azienda Ospedaliera Pugliese-Ciaccio, Catanzaro, Italy
| | - Gaetano Rocco
- Thoracic Surgery, Thoracic Department, Istituto Nazionale Tumori, "Fondazione G.Pascale" - IRCCS, Napoli, Italy
| | - Roberto Bianco
- Department of Clinical Medicine and Surgery, University Federico II, Napoli, Italy
| | - Francesco Perrone
- Clinical Trials Unit, Istituto Nazionale Tumori, "Fondazione G.Pascale" - IRCCS, Napoli, Italy
| | - Alessandro Morabito
- Medical Oncology Unit, Thoracic Department, Istituto Nazionale Tumori, "Fondazione G. Pascale" - IRCCS, Napoli, Italy.
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Engle JA, Kolesar JM. Afatinib: A first-line treatment for selected patients with metastatic non-small-cell lung cancer. Am J Health Syst Pharm 2015; 71:1933-8. [PMID: 25349236 DOI: 10.2146/ajhp130654] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
PURPOSE The pharmacology, pharmacokinetics, clinical efficacy, safety, adverse effects, dosage and administration, and role in therapy of afatinib in the management of non-small-cell lung cancer (NSCLC) are reviewed. SUMMARY Afatinib (Gilotrif, Boehringer Ingelheim) is a novel oral tyrosine kinase inhibitor (TKI) recently approved for the first-line treatment of patients with NSCLC whose tumors are driven by activating mutations of genes coding for epidermal growth factor receptor (EGFR). Afatinib is also an inhibitor of a specific EGFR mutation (T790M) that causes resistance to first-generation EGFR-targeted TKIs in about half of patients receiving those drugs. The recommended dosage is 40 mg once daily. In a Phase III trial completed last year, patients with EGFR-mutated NSCLC who were treated with afatinib had a twofold higher response rate than those receiving standard combination chemotherapy (56% versus 23%) and significantly longer progression-free survival (11.0 months versus 5.6 months). Other studies indicated that afatinib may offer advantages over standard chemotherapy for NSCLC in terms of enhanced symptom control and quality of life and is modestly effective in cases involving EGFRT790M-related acquired resistance to the TKIs erlotinib and gefitinib. Among clinical trial participants, afatinib was generally well tolerated, with the most common grade I or II adverse events being diarrhea and rash or acne; grade III or IV events were infrequent. CONCLUSION Afatinib is a novel TKI that is efficacious and well tolerated in patients with NSCLC associated with activating EGFR mutations, including cases involving the T790M resistance mutation. It has possible applications in other EGFR mutation- positive cancers.
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Affiliation(s)
- Jeff A Engle
- Jeff A. Engle, B.S., is a Pharm.D. student, School of Pharmacy, University of Wisconsin (UW)-Madison, Madison. Jill M. Kolesar, Pharm.D., BCPS, FCCP, is Professor, School of Pharmacy, UW-Madison, and Faculty Supervisor, Analytical Laboratory for Pharmacokinetics, Pharmacodynamics, and Pharmacogenomics, UW Carbone Comprehensive Cancer Center, Madison
| | - Jill M Kolesar
- Jeff A. Engle, B.S., is a Pharm.D. student, School of Pharmacy, University of Wisconsin (UW)-Madison, Madison. Jill M. Kolesar, Pharm.D., BCPS, FCCP, is Professor, School of Pharmacy, UW-Madison, and Faculty Supervisor, Analytical Laboratory for Pharmacokinetics, Pharmacodynamics, and Pharmacogenomics, UW Carbone Comprehensive Cancer Center, Madison.
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Abstract
First-generation, reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), erlotinib and gefitinib, represented an important addition to the treatment armamentarium for non-small-cell lung cancer (NSCLC) patients with activating EGFR mutations. However, all patients inevitably develop acquired resistance to these agents, primarily due to secondary EGFR mutations, molecular aberrations affecting other signaling pathways, or transformation to small-cell histology. It was hypothesized that development of second-generation TKIs with broader inhibitory profiles could confer longer-lasting clinical activity and overcome acquired resistance to first-generation inhibitors. Here, we review the development of afatinib, an irreversible ErbB family blocker that potently inhibits signaling of all homodimers and heterodimers formed by the EGFR, human epidermal growth factor receptor (HER)-2, HER3, and HER4 receptors. In two phase III trials in patients with EGFR mutation-positive NSCLC, first-line afatinib significantly improved progression-free survival (PFS) and health-related quality of life versus standard-of-care chemotherapy. Moreover, in preplanned sub-analyses, afatinib significantly improved overall survival in patients harboring EGFR Del19 mutations. Afatinib has also demonstrated clinical activity in NSCLC patients who had progressed on erlotinib/gefitinib, particularly when combined with cetuximab, and offers 'treatment beyond progression' benefit when combined with paclitaxel versus chemotherapy alone. Furthermore, a recent phase III study demonstrated that PFS was significantly improved with afatinib versus erlotinib for the second-line treatment of patients with squamous cell carcinoma of the lung. The activity of afatinib in both first-line and relapsed/refractory settings may reflect its ability to irreversibly inhibit all ErbB family members. Afatinib has a well-defined safety profile with characteristic gastrointestinal (diarrhea, stomatitis) and cutaneous (rash/acne) adverse events.
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Affiliation(s)
- Vera Hirsh
- McGill Department of Oncology, Royal Victoria Hospital, 687 Pine Avenue W., Montreal, QC, H3A 1A1, Canada,
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26
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Jia Y, Ali SM, Saad S, Chan CA, Miller VA, Halmos B. Successful treatment of a patient with Li-Fraumeni syndrome and metastatic lung adenocarcinoma harboring synchronous EGFR L858R and ERBB2 extracellular domain S310F mutations with the pan-HER inhibitor afatinib. Cancer Biol Ther 2014; 15:970-4. [PMID: 24835218 PMCID: PMC4119081 DOI: 10.4161/cbt.29173] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2014] [Revised: 05/01/2014] [Accepted: 05/08/2014] [Indexed: 11/19/2022] Open
Abstract
We report the case of a young, never-smoker woman with Li-Fraumeni syndrome and advanced lung adenocarcinoma refractory to multiple lines of conventional chemotherapy and negative for actionable alterations by routine testing. Comprehensive genomic profiling by clinical-grade next generation sequencing was performed on 3320 exons of 184 cancer-related genes and 37 introns of 14 genes frequently rearranged in cancer. The tumor was found to harbor both EGFR L858R and ERBB2 S310F alterations and also tested positive for a known TP53 germline mutation. The presence of the EGFR mutation was further validated by direct sequencing. Based on these results, a dual EGFR/ERBB2 inhibitor, afatinib, was chosen for treatment. The patient achieved a rapid, complete, and durable response to afatinib monotherapy, both clinically and radiographically. The treatment was very well tolerated. This unique case raises practical questions as to the challenges of molecular testing and highlights the potential association of p53 mutations with concurrent EGFR and ERBB2 aberrations. As this case powerfully illustrates, the combination of broad genomic profiling and targeted therapy guided by mutational analysis offers the possibility of precision management of refractory advanced adenocarcinoma in the background of neoplastic syndromes.
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Affiliation(s)
- Yuxia Jia
- New York Presbyterian Hospital-Columbia University Medical Center; New York, NY USA
| | - Siraj M Ali
- Foundation Medicine, Inc.; Cambridge, MA USA
| | - Shumaila Saad
- New York Presbyterian Hospital-Columbia University Medical Center; New York, NY USA
| | - Courtney A Chan
- New York Presbyterian Hospital-Columbia University Medical Center; New York, NY USA
| | | | - Balazs Halmos
- New York Presbyterian Hospital-Columbia University Medical Center; New York, NY USA
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HER2/neu: an increasingly important therapeutic target. Part 1: basic biology & therapeutic armamentarium. ACTA ACUST UNITED AC 2014. [DOI: 10.4155/cli.14.57] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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Passaro A, Cortesi E, de Marinis F. Second-line treatment of non-small-cell lung cancer: chemotherapy or tyrosine kinase inhibitors? Expert Rev Anticancer Ther 2014; 11:1587-97. [DOI: 10.1586/era.11.120] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Abstract
The ERBB family of receptor tyrosine kinases has a central role in the tumorigenesis of many types of solid tumour. Various therapeutics targeting these receptors have been approved for the treatment of several cancers. Considerable preclinical data have shown that the administration of two inhibitors against an individual ERBB family member--particularly epidermal growth factor receptor (EGFR) or ERBB2--leads to markedly higher antitumour activity than the administration of single agents. This Opinion article describes the preclinical and clinical performance of these dual-targeting approaches, discusses the key mechanisms that mediate their increased efficacy and highlights areas for ongoing investigation.
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Affiliation(s)
- Niall Tebbutt
- Ludwig Oncology Unit, Austin Health, Studley Road, Heidelberg, Victoria 3084, Australia
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30
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Xiang M, Lei K, Fan W, Lin Y, He G, Yang M, Chen L, Mo Y. In silico identification of EGFR-T790M inhibitors with novel scaffolds: start with extraction of common features. Drug Des Devel Ther 2013; 7:789-839. [PMID: 23990708 PMCID: PMC3748928 DOI: 10.2147/dddt.s41305] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Background Epidermal growth factor receptor (EGFR) is an attractive therapeutic target for a number of human tumors including non-small cell lung cancer (NSCLC). Most patients with NSCLC and somatic mutations have shown a dramatic initial clinical response to reversible EGFR inhibitors. The clinical efficacy of reversible inhibitors is, however, ultimately limited due to the emergence of drug resistance, which is usually conferred by the EGFR T790M mutation. Importantly, irreversible, synthetic small molecule inhibitors are currently evaluated and some of them have been shown to overcome the acquired resistance that is oftentimes observed in these patients. Thus far, irreversible EGFR inhibitors as a drug class have not received regulatory approval due in part to their poor effectiveness at clinically achievable concentrations. Therefore, there is an urgent need to discover and develop novel, potent irreversible inhibitors against the EGFR T790M mutation. Material and methods In the following study, we report a novel “hybrid strategy” to identify irreversible EGFR inhibitors with active scaffolds starting with the identification and extraction of a common chemical reactive feature and a pharmacophore feature. The chemical reactive feature was elucidated by investigating 138 currently known irreversible inhibitors at B3LYP/6-31G(d) level using the density function theory method. The pharmacophore feature was extracted from the same inhibitors using pharmacophore modeling. Based on these unique features, two constraints were set while calibrating the protocols of in silico screening. Compounds bearing these specific features were obtained from the National Cancer Institute diversity database to form our subsequent library. Finally, a structure based virtual screening against the library was conducted using standard protocols validated in our lab. Results Twenty-eight candidate compounds that demonstrated antitumor activity and that had novel scaffolds different from commonly known quinazoline/quinoline analogs were obtained. The interaction modes between three representative candidates and our model system are similar to that between the model system and the reference compound T-001, which has previously been reported to be one of the most potent of the 138 irreversible inhibitors. Conclusion The hybrid strategy starting with the extraction of common features is an effective approach to design potential irreversible inhibitors with novel scaffolds and therefore to obtain lead molecules in the selection process. These candidates possessing unique scaffolds have a strong likelihood to act as further starting points in the preclinical development of potent irreversible T790M EGFR inhibitors.
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Affiliation(s)
- Mingli Xiang
- State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, #1 Keyuan Road 4, Chengdu, People's Republic of China.
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Mechanisms of resistance to EGFR tyrosine kinase inhibitors gefitinib/erlotinib and to ALK inhibitor crizotinib. Lung Cancer 2013; 81:328-336. [PMID: 23809060 DOI: 10.1016/j.lungcan.2013.05.020] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2013] [Revised: 04/24/2013] [Accepted: 05/29/2013] [Indexed: 01/15/2023]
Abstract
The discovery of several molecular alterations that underlie non-small cell lung cancer (NSCLC) pathogenesis has led to the development of targeted therapies. In particular, gefitinib and erlotinib have become the standard of care in patients harboring epidermal growth factor receptor mutations, while crizotinib showed an impressive efficacy in patients with ALK-positive NSCLC. Nevertheless, the occurrence of clinical resistance limits the long term results of these novel agents. The identification of the molecular mechanisms responsible for acquired resistance to targeted therapy is crucial in order to pursue the creation of rational strategies to overcome resistance. In the current review, we will focus on the acquired resistance mechanisms to EGFR-TKIs and crizotinib and the therapeutic strategies currently under study to overcome resistance.
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Roengvoraphoj M, Tsongalis GJ, Dragnev KH, Rigas JR. Epidermal growth factor receptor tyrosine kinase inhibitors as initial therapy for non-small cell lung cancer: focus on epidermal growth factor receptor mutation testing and mutation-positive patients. Cancer Treat Rev 2013; 39:839-50. [PMID: 23768755 DOI: 10.1016/j.ctrv.2013.05.001] [Citation(s) in RCA: 88] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2012] [Revised: 05/02/2013] [Accepted: 05/04/2013] [Indexed: 01/24/2023]
Abstract
Activation of the epidermal growth factor receptor (EGFR) pathway has been implicated in tumorigenesis in non-small cell lung cancer (NSCLC), the most common type of lung cancer. As a result, EGFR has become a key focus for the development of personalized therapy, with several molecular biomarkers having been investigated as potential predictors of response with EGFR tyrosine kinase inhibitors (TKIs) in NSCLC (e.g., EGFR expression, EGFR gene copy gain, and EGFR mutations). Of these, activating mutations in EGFR have thus far given the most consistent results based on the available evidence from preclinical studies and clinical trials. In an attempt to identify patients who are most likely to benefit from treatment with EGFR TKIs, EGFR mutation testing is being increasingly utilized in clinical practice. Currently in the United States, no EGFR TKI or accompanying mutational test is approved for the identification and first-line treatment of patients with advanced NSCLC. However, the first-generation EGFR TKIs, erlotinib and gefitinib, as well as investigational ErbB family TKIs and EGFR mutation testing methods are being evaluated in this setting. This review will discuss EGFR mutation testing as a biomarker of response to EGFR TKIs and the evolution of EGFR mutational analysis in NSCLC. Completed and ongoing clinical trials evaluating currently available or investigational EGFR TKIs as first-line therapy in molecularly and clinically selected patients with NSCLC, with a focus on trials in patients whose tumors have EGFR mutations, will also be reviewed.
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Affiliation(s)
- Monic Roengvoraphoj
- Comprehensive Thoracic Oncology Program, Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756-0001, USA; The Geisel School of Medicine at Dartmouth, One Rope Ferry Road, Hanover, NH 03755-1404, USA.
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Langer CJ, Mok T, Postmus PE. Targeted agents in the third-/fourth-line treatment of patients with advanced (stage III/IV) non-small cell lung cancer (NSCLC). Cancer Treat Rev 2013; 39:252-60. [DOI: 10.1016/j.ctrv.2012.05.003] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2012] [Revised: 05/08/2012] [Accepted: 05/10/2012] [Indexed: 12/22/2022]
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Ryczak J, Papini M, Lader A, Nasereddin A, Kopelyanskiy D, Preu L, Jaffe CL, Kunick C. 2-Arylpaullones are selective antitrypanosomal agents. Eur J Med Chem 2013; 64:396-400. [PMID: 23648975 DOI: 10.1016/j.ejmech.2013.03.065] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2013] [Revised: 03/27/2013] [Accepted: 03/28/2013] [Indexed: 01/08/2023]
Abstract
Antileishmanial paullone-chalcone hybrid molecules display antiparasitic activity against Trypanosoma brucei rhodesiense blood stream forms, albeit with low selectivity against human THP-1 cells. In order to develop less toxic analogues, paullones with acrylamide or aryl substituents in 2-position were synthesized, of which the latter exhibited potent antiparasitic activity with excellent selectivity profiles. The most potent compound identified in this study was 9-tert-butyl-2-(4-morpholinophenyl)paullone (3i) which inhibited the parasites at submicromolar concentrations (GI50 = 510 nM) with a selectivity index of 157.
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Affiliation(s)
- Jasmin Ryczak
- Technische Universität Braunschweig, Institut für Medizinische und Pharmazeutische Chemie, Beethovenstraße 55, D-38106 Braunschweig, Germany
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Chen G, Noor A, Kronenberger P, Teugels E, Umelo IA, De Grève J. Synergistic effect of afatinib with su11274 in non-small cell lung cancer cells resistant to gefitinib or erlotinib. PLoS One 2013; 8:e59708. [PMID: 23527257 PMCID: PMC3601073 DOI: 10.1371/journal.pone.0059708] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2012] [Accepted: 02/17/2013] [Indexed: 11/19/2022] Open
Abstract
Epidermal growth factor receptor (EGFR) and c-MET receptors are expressed on many non-small cell lung cancer (NSCLC) cells. Current single agent therapeutic targeting of a mutant EGFR has a high efficacy in the clinic, but is not curative. Here, we investigated the combination of targeting EGFR and c-MET pathways in NSCLC cells resistant to receptor tyrosine kinase inhibitors (TKIs), using RNA interference and inhibition by TKIs. Different NSCLC cell lines with various genomic characteristics (H358, H1650 and H1975) were transfected with EGFR-specific-siRNA, T790M-specific-siRNA, c-MET siRNA or the combination. Subsequently EGFR TKIs (gefitinib, erlotinib or afatinib) or monoclonal antibody cetuximab were combined respectively with the c-MET-specific TKI su11274 in NSCLC cell lines. The cell proliferation, viability, caspase-3/7 activity and apoptotic morphology were monitored by spectrophotometry, fluorimetry and fluorescence microscopy. The combined effect of EGFR TKIs, or cetuximab and su11274, was evaluated using a combination index. The results showed that the cell lines that were relatively resistant to EGFR TKIs, especially the H1975 cell line containing the resistance T790M mutation, were found to be more sensitive to EGFR-specific-siRNA. The combination of EGFR siRNA plus c-MET siRNA enhanced cell growth inhibition, apoptosis induction and inhibition of downstream signaling in EGFR TKI resistant H358, H1650 and H1975 cells, despite the absence of activity of the c-MET siRNA alone. EGFR TKIs or cetuximab plus su11274 were also consistently superior to either agent alone. The strongest biological effect was observed when afatinib, an irreversible pan-HER blocker was combined with su11274, which achieved a synergistic effect in the T790M mutant H1975 cells. In a conclusion, our findings offer preclinical proof of principle for combined inhibition as a promising treatment strategy for NSCLC, especially for patients in whom current EGFR-targeted treatments fail due to the presence of the T790M-EGFR-mutation or high c-MET expression.
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Affiliation(s)
- Gang Chen
- Department of Pathology, First Affiliated Hospital, Guangxi Medical University, Nanning Guangxi, People's Republic of China
- Laboratory of Medical and Molecular Oncology, Department of Medical Oncology, Oncology Center, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium
| | - Alfiah Noor
- Laboratory of Medical and Molecular Oncology, Department of Medical Oncology, Oncology Center, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium
| | - Peter Kronenberger
- Laboratory of Medical and Molecular Oncology, Department of Medical Oncology, Oncology Center, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium
- Laboratory for Biotechnology, Departement Gezondheidszorg, Erasmushogeschool Brussel, Brussels, Belgium
| | - Erik Teugels
- Laboratory of Medical and Molecular Oncology, Department of Medical Oncology, Oncology Center, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium
| | - Ijeoma Adaku Umelo
- Laboratory of Medical and Molecular Oncology, Department of Medical Oncology, Oncology Center, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium
| | - Jacques De Grève
- Laboratory of Medical and Molecular Oncology, Department of Medical Oncology, Oncology Center, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Brussels, Belgium
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Nelson V, Ziehr J, Agulnik M, Johnson M. Afatinib: emerging next-generation tyrosine kinase inhibitor for NSCLC. Onco Targets Ther 2013; 6:135-43. [PMID: 23493883 PMCID: PMC3594037 DOI: 10.2147/ott.s23165] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
The discovery of epidermal growth-factor receptor (EGFR)-activating mutations and the introduction of oral EGFR tyrosine kinase inhibitors (EGFR-TKIs) have expanded the treatment options for patients with non-small cell lung cancer. The first two reversible EGFR-TKIs, erlotinib and gefitinib, are approved for use in the first-line setting in patients with known EGFR-activating mutations and in the second- and third-line settings for all NSCLC patients. These first-generation EGFR-TKIs improve progression-free survival when compared to chemotherapy in patients with EGFR-activating mutations in the first-line setting. However, nearly all patients develop resistance to EGFR-directed agents. There is a need for further therapy options for patients with disease progression after treatment with reversible EGFR-TKIs. Afatinib is an irreversible ErbB family blocker that inhibits EGFR, HER2, and HER4. In vitro and in vivo, afatinib have shown increased inhibition of the common EGFR-activating mutations as well as the T790M resistance mutation when compared to erlotinib and gefitinib. Clinically, afatinib has been evaluated in the LUX-Lung series of trials, with improvement in progression-free survival reported in patients with EGFR-activating mutations in both first- and second-/third-line settings when compared to chemotherapy. Further investigation is needed to determine the precise role that afatinib will play in the treatment of patients with non-small cell lung cancer and EGFR-activating mutations.
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Affiliation(s)
- Valerie Nelson
- Robert H Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
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Tang J, Salama R, Gadgeel SM, Sarkar FH, Ahmad A. Erlotinib resistance in lung cancer: current progress and future perspectives. Front Pharmacol 2013; 4:15. [PMID: 23407898 PMCID: PMC3570789 DOI: 10.3389/fphar.2013.00015] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2012] [Accepted: 01/25/2013] [Indexed: 12/26/2022] Open
Abstract
Lung cancer is the most common cancer in the world. Despite modern advancements in surgeries, chemotherapies, and radiotherapies over the past few years, lung cancer still remains a very difficult disease to treat. This has left the death rate from lung cancer victims largely unchanged throughout the past few decades. A key cause for the high mortality rate is the drug resistance that builds up for patients being currently treated with the chemotherapeutic agents. Although certain chemotherapeutic agents may initially effectively treat lung cancer patients, there is a high probability that there will be a reoccurrence of the cancer after the patient develops resistance to the drug. Erlotinib, the epidermal growth factor receptor (EGFR)-targeting tyrosine kinase inhibitor, has been approved for localized as well as metastatic non-small cell lung cancer where it seems to be more effective in patients with EGFR mutations. Resistance to erlotinib is a common observation in clinics and this review details our current knowledge on the subject. We discuss the causes of such resistance as well as innovative research to overcome it. Evidently, new chemotherapy strategies are desperately needed in order to better treat lung cancer patients. Current research is investigating alternative treatment plans to enhance the chemotherapy that is already offered. Better insight into the molecular mechanisms behind combination therapy pathways and even single molecular pathways may help improve the efficacy of the current treatment options.
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Affiliation(s)
- Joy Tang
- Department of Pathology, Karmanos Cancer Institute, Wayne State University School of MedicineDetroit, MI, USA
| | - Rasha Salama
- Department of Pathology, Karmanos Cancer Institute, Wayne State University School of MedicineDetroit, MI, USA
| | - Shirish M. Gadgeel
- Department of Oncology, Karmanos Cancer Institute, Wayne State University School of MedicineDetroit, MI, USA
| | - Fazlul H. Sarkar
- Department of Pathology, Karmanos Cancer Institute, Wayne State University School of MedicineDetroit, MI, USA
- Department of Oncology, Karmanos Cancer Institute, Wayne State University School of MedicineDetroit, MI, USA
| | - Aamir Ahmad
- Department of Pathology, Karmanos Cancer Institute, Wayne State University School of MedicineDetroit, MI, USA
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Vermorken JB, Rottey S, Ehrnrooth E, Pelling K, Lahogue A, Wind S, Machiels JP. A phase Ib, open-label study to assess the safety of continuous oral treatment with afatinib in combination with two chemotherapy regimens: cisplatin plus paclitaxel and cisplatin plus 5-fluorouracil, in patients with advanced solid tumors. Ann Oncol 2013; 24:1392-400. [PMID: 23293114 DOI: 10.1093/annonc/mds633] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND In this phase Ib, dose-escalation study, the oral irreversible ErbB family blocker afatinib (BIBW 2992) was combined with cisplatin (Cadila Healthcare Ltd, Ahmedabad, India) 50 or 75 mg/m(2)/paclitaxel (Bristol-Myers Squibb Pharmaceuticals Ltd, New York, USA) (Taxol)175 mg/m(2) (regimen A) or cisplatin 75-100 mg/m(2)/5-fluorouracil 750-1000 mg/m(2) (regimen B) in patients with advanced solid tumors. PATIENTS AND METHODS The primary objective was to assess dose-limiting toxicities (DLTs) during cycle 1 for each regimen, from which the maximum tolerated dose (MTD) was determined. Patients received once daily oral afatinib 20, 30, 40 or 50 mg in 21-day cycles (3 + 3 design). RESULTS The MTD for afatinib in regimens A (n = 26) and B (n = 21) was determined as 20 mg and 30 mg following DLTs in five and four patients in cycle 1, respectively. Most frequent adverse events (AEs, any grade) were diarrhea and nausea. Disease control was observed in 54% and 29% of patients in regimens A and B, respectively. Plasma sampling suggested no relevant pharmacokinetic interaction between afatinib and the chemotherapeutic agents. CONCLUSIONS The MTD of afatinib was 20 mg with cisplatin-paclitaxel and 30 mg with cisplatin-5-fluorouracil. Pre-emptive management of side-effects is important to maintain adequate safety and tolerability. Both combinations showed antitumor activity across tumor types and lines of prior treatment.
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Affiliation(s)
- J B Vermorken
- Department of Medical Oncology, Antwerp University Hospital, Edegem.
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De Grève J, Decoster L, van Brummelen D, Geers C, Schallier D. Is there a third line option after chemotherapy and TKI failure in advanced non-small cell lung cancer? Transl Lung Cancer Res 2012; 1:152-4. [PMID: 25806173 PMCID: PMC4367571 DOI: 10.3978/j.issn.2218-6751.2012.06.04] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2012] [Accepted: 06/11/2012] [Indexed: 12/18/2022]
Affiliation(s)
- Jacques De Grève
- Department of Medical Oncology, Oncologisch Centrum, UZ Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium
| | - Lore Decoster
- Department of Medical Oncology, Oncologisch Centrum, UZ Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium
| | - David van Brummelen
- Department of Medical Oncology, Oncologisch Centrum, UZ Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium
| | - Caroline Geers
- Department of Medical Oncology, Oncologisch Centrum, UZ Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium
| | - Denis Schallier
- Department of Medical Oncology, Oncologisch Centrum, UZ Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium
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Chen G, Kronenberger P, Teugels E, Umelo IA, De Grève J. Targeting the epidermal growth factor receptor in non-small cell lung cancer cells: the effect of combining RNA interference with tyrosine kinase inhibitors or cetuximab. BMC Med 2012; 10:28. [PMID: 22436374 PMCID: PMC3334713 DOI: 10.1186/1741-7015-10-28] [Citation(s) in RCA: 109] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2011] [Accepted: 03/21/2012] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The epidermal growth factor receptor (EGFR) is a validated therapeutic target in non-small cell lung cancer (NSCLC). However, current single agent receptor targeting does not achieve a maximal therapeutic effect, and some mutations confer resistance to current available agents. In the current study we have examined, in different NSCLC cell lines, the combined effect of RNA interference targeting the EGFR mRNA, and inactivation of EGFR signaling using different receptor tyrosine kinase inhibitors (TKIs) or a monoclonal antibody cetuximab. METHODS NSCLC cells (cell lines HCC827, H292, H358, H1650, and H1975) were transfected with EGFR siRNA and/or treated with the TKIs gefitinib, erlotinib, and afatinib, and/or with the monoclonal antibody cetuximab. The reduction of EGFR mRNA expression was measured by real-time quantitative RT-PCR. The down-regulation of EGFR protein expression was measured by western blot, and the proliferation, viability, caspase3/7 activity, and apoptotic morphology were monitored by spectrophotometry, fluorimetry, and fluorescence microscopy. The combined effect of EGFR siRNA and different drugs was evaluated using a combination index. RESULTS EGFR-specific siRNA strongly inhibited EGFR protein expression almost equally in all cell lines and inhibited cell growth and induced cell apoptosis in all NSCLC cell lines studied, albeit with a different magnitude. The effects on growth obtained with siRNA was strikingly different from the effects obtained with TKIs. The effects of siRNA probably correlate with the overall oncogenic significance of the receptor, which is only partly inhibited by the TKIs. The cells which showed weak response to TKIs, such as the H1975 cell line containing the T790M resistance mutation, were found to be responsive to siRNA knockdown of EGFR, as were cell lines with downstream TKI resistance mutations. The cell line HCC827, harboring an exon 19 deletion mutation, was more than 10-fold more sensitive to TKI proliferation inhibition and apoptosis induction than any of the other cell lines. Cetuximab alone had no relevant in vitro activity at concentrations obtainable in the clinic. The addition of EGFR siRNA to either TKIs or cetuximab additively enhanced growth inhibition and induction of apoptosis in all five cell lines, independent of the EGFR mutation status (wild-type or sensitizing mutation or resistant mutation). The strongest biological effect was observed when afatinib was combined with an EGFR-specific siRNA. CONCLUSIONS EGFR knockdown by siRNA further decreases the cell growth of lung cancer cells that are treated with TKIs or cetuximab alone, confirming that single agent drug targeting does not achieve a maximal biological effect. The siRNA inhibits EGFR oncogenic activity that bypasses downstream "resistance" mutations such as KRAS and PTEN. The combined treatment of siRNA and EGFR inhibitory agents is additive. The combination of a potent, irreversible kinase inhibitor such as afatinib, with EGFR-specific siRNAs should be further investigated as a new strategy in the treatment of lung cancer and other EGFR dependent cancers, including those with downstream resistance mutations.
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Affiliation(s)
- Gang Chen
- Laboratory of Medical and Molecular Oncology and Department of Medical Oncology, Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel, Laarbeeklaan 101, 1090, Brussels, Belgium
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Brugger W, Thomas M. EGFR-TKI resistant non-small cell lung cancer (NSCLC): new developments and implications for future treatment. Lung Cancer 2012; 77:2-8. [PMID: 22281074 DOI: 10.1016/j.lungcan.2011.12.014] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2011] [Revised: 12/23/2011] [Accepted: 12/24/2011] [Indexed: 10/14/2022]
Abstract
Treatment with receptor-tyrosine kinase inhibitors (TKIs) has improved progression-free and overall survival in patients with advanced non-small cell lung cancer (NSCLC). One major target for treatment with TKI is the epidermal growth factor receptor (EGFR), particularly in patients harboring activating mutations. However, despite initial responses and long lasting remissions, the development of secondary resistance inevitably leads to treatment failure. Analyzing recent data from various phase II/III trials it seems obvious that the single mode of action of gefitinib or erlotinib can provide temporary success only. Both preclinical and clinical evidence suggest that irreversible TKIs such as afatinib or PF00299804, or combined approaches using multiple kinase inhibition (e.g. EGFR and MET) and vertical inhibition by combination of small molecules and antibodies, seem to be more promising and will be the prevailing concepts to overcome secondary EGFR-TKI resistance for the near future.
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Affiliation(s)
- Wolfram Brugger
- Medical Center II, Department of Hematology/Oncology, Schwarzwald-Baar Clinic, Academic Teaching Hospital University of Freiburg, Villingen-Schwenningen, Germany.
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Abstract
Afatinib (BIBW 2992), a novel aniline-quinazoline derivative, irreversibly and equipotently targets the intrinsic kinase activity of all active ErbB receptor family members. Preclinical results show that afatinib is effective in lung cancer models, including those with EGF receptor (EGFR) mutations resistant to reversible first-generation EGFR inhibitors. Afatinib is being investigated in the LUX-Lung program, which will evaluate afatinib as a first-line treatment in patients with EGFR-activating mutations (LUX-Lung 2, 3 and 6) and as a second- or third-line treatment in patients that have acquired resistance to gefitinib and/or erlotinib (LUX-Lung 1, 4 and 5). LUX-Lung 1 and 2 have demonstrated, within their respective target groups, a significant increase in the disease control rate of 58 and 86%, respectively, and significant prolongation of progression-free survival. Further Phase III clinical trials are currently ongoing to assess afatinib in combination with paclitaxel (LUX-Lung 5), and compared with cisplatin/pemetrexed (LUX-Lung 3) or cisplatin/gemcitabine (LUX-Lung 6).
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Affiliation(s)
- Vera Hirsh
- McGill University, Department of Medicine & Oncology, Royal Victoria Hospital, Montreal, Quebec, Canada.
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44
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Buettner R, Corzano R, Rashid R, Lin J, Senthil M, Hedvat M, Schroeder A, Mao A, Herrmann A, Yim J, Li H, Yuan YC, Yakushijin K, Yakushijin F, Vaidehi N, Moore R, Gugiu G, Lee TD, Yip R, Chen Y, Jove R, Horne D, Williams JC. Alkylation of cysteine 468 in Stat3 defines a novel site for therapeutic development. ACS Chem Biol 2011; 6:432-43. [PMID: 21226522 DOI: 10.1021/cb100253e] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Stat3 is a latent transcription factor that promotes cell survival and proliferation and is often constitutively active in multiple cancers. Inhibition of Stat3 signaling pathways suppresses cell survival signals and leads to apoptosis in cancer cells, suggesting direct inhibition of Stat3 function is a viable therapeutic approach. Herein, we identify a small molecule, C48, as a selective Stat3-family member inhibitor. To determine its mechanism of action, we used site-directed mutagenesis and multiple biochemical techniques to show that C48 alkylates Cys468 in Stat3, a residue at the DNA-binding interface. We further demonstrate that C48 blocks accumulation of activated Stat3 in the nucleus in tumor cell lines that overexpress active Stat3, leading to impressive inhibition of tumor growth in mouse models. Collectively, these findings suggest Cys468 in Stat3 represents a novel site for therapeutic intervention and demonstrates the promise of alkylation as a potentially effective chemical approach for Stat3-dependent cancers.
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Affiliation(s)
- Ralf Buettner
- Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California 91010, United States
| | - Renzo Corzano
- Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California 91010, United States
| | - Rumana Rashid
- Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California 91010, United States
| | - Jianping Lin
- Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California 91010, United States
| | - Maheswari Senthil
- Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California 91010, United States
| | - Michael Hedvat
- Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California 91010, United States
| | - Anne Schroeder
- Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California 91010, United States
| | - Allen Mao
- Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California 91010, United States
| | - Andreas Herrmann
- Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California 91010, United States
| | - John Yim
- Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California 91010, United States
| | - Hongzhi Li
- Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California 91010, United States
| | - Yate-Ching Yuan
- Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California 91010, United States
| | - Kenichi Yakushijin
- Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California 91010, United States
| | - Fumiko Yakushijin
- Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California 91010, United States
| | - Nagarajan Vaidehi
- Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California 91010, United States
| | - Roger Moore
- Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California 91010, United States
| | - Gabriel Gugiu
- Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California 91010, United States
| | - Terry D. Lee
- Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California 91010, United States
| | - Richard Yip
- Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California 91010, United States
| | - Yuan Chen
- Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California 91010, United States
| | - Richard Jove
- Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California 91010, United States
| | - David Horne
- Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California 91010, United States
| | - John C. Williams
- Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, California 91010, United States
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45
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Leproult E, Barluenga S, Moras D, Wurtz JM, Winssinger N. Cysteine mapping in conformationally distinct kinase nucleotide binding sites: application to the design of selective covalent inhibitors. J Med Chem 2011; 54:1347-55. [PMID: 21322567 DOI: 10.1021/jm101396q] [Citation(s) in RCA: 151] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Kinases have emerged as one of the most prolific therapeutic targets. An important criterion in the therapeutic success of inhibitors targeting the nucleotide binding pocket of kinases is the inhibitor residence time. Recently, covalent kinase inhibitors have attracted attention since they confer terminal inhibition and should thus be more effective than reversible inhibitors with transient inhibition. The most robust approach to design irreversible inhibitors is to capitalize on the nucleophilicity of a cysteine thiol group present in the target protein. Herein, we report a systematic analysis of cysteine residues present in the nucleotide binding site of kinases, which could be harnessed for irreversible inhibition, taking into consideration the different kinase conformations. We demonstrate the predictive power of this analysis with the design and validation of an irreversible inhibitor of KIT/PDGFR kinases. This is the first example of a covalent kinase inhibitor that combines a pharmacophore addressing the DFG-out conformation with a covalent trap.
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Affiliation(s)
- Emeline Leproult
- Institut de Génétique et de Biologie Moléculaire et Cellulaire-CNRS, UMR 7104, INSERM, U964, 1 rue Laurent Fries, Université de Strasbourg, 67400 Illkirch, France
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46
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Morère JF. Personalized medicine in lung adenocarcinoma: no longer a hope or a passing fashion, but a new reality. Target Oncol 2010; 5:229-30. [PMID: 21120632 DOI: 10.1007/s11523-010-0166-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2010] [Accepted: 11/08/2010] [Indexed: 11/29/2022]
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