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Barzi A, Weipert CM, Espenschied CR, Raymond VM, Wang-Gillam A, Nezami MA, Gordon EJ, Mahadevan D, Mody K. ERBB2 (HER2) amplifications and co-occurring KRAS alterations in the circulating cell-free DNA of pancreatic ductal adenocarcinoma patients and response to HER2 inhibition. Front Oncol 2024; 14:1339302. [PMID: 38406801 PMCID: PMC10885695 DOI: 10.3389/fonc.2024.1339302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Accepted: 01/16/2024] [Indexed: 02/27/2024] Open
Abstract
Purpose Despite accumulating data regarding the genomic landscape of pancreatic ductal adenocarcinoma (PDAC), olaparib is the only biomarker-driven FDA-approved targeted therapy with a PDAC-specific approval. Treating ERBB2(HER2)-amplified PDAC with anti-HER2 therapy has been reported with mixed results. Most pancreatic adenocarcinomas have KRAS alterations, which have been shown to be a marker of resistance to HER2-targeted therapies in other malignancies, though the impact of these alterations in pancreatic cancer is unknown. We describe two cases of ERBB2-amplified pancreatic cancer patients treated with anti-HER2 therapy and provide data on the frequency of ERBB2 amplifications and KRAS alterations identified by clinical circulating cell-free DNA testing. Methods De-identified molecular test results for all patients with pancreatic cancer who received clinical cell-free circulating DNA analysis (Guardant360) between 06/2014 and 01/2018 were analyzed. Cell-free circulating DNA analysis included next-generation sequencing of up to 73 genes, including select small insertion/deletions, copy number amplifications, and fusions. Results Of 1,791 patients with pancreatic adenocarcinoma, 36 (2.0%) had an ERBB2 amplification, 26 (72.2%) of whom had a KRAS alteration. Treatment data were available for seven patients. Two were treated with anti-HER2 therapy after their cell-free circulating DNA result, with both benefiting from therapy, including one with a durable response to trastuzumab and no KRAS alteration detected until progression. Conclusion Our case series illustrates that certain patients with ERBB2-amplified pancreatic adenocarcinoma may respond to anti-HER2 therapy and gain several months of prolonged survival. Our data suggests KRAS mutations as a possible mechanism of primary and acquired resistance to anti-HER2 therapy in pancreatic cancer. Additional studies are needed to clarify the role of KRAS in resistance to anti-HER2 therapy.
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Affiliation(s)
- Afsaneh Barzi
- Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, Duarte, CA, United States
| | | | | | | | - Andrea Wang-Gillam
- Division of Oncology, Siteman Cancer Center, St. Louis, MO, United States
| | | | - Eva J. Gordon
- Private Health Management, Inc., Los Angeles, CA, United States
| | - Daruka Mahadevan
- Division of Hematology and Oncology, Department of Medicine, University of Texas Health, San Antonio, San Antonio, TX, United States
| | - Kabir Mody
- Division of Hematology-Oncology, Department of Medicine, Mayo Clinic, Jacksonville, FL, United States
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Masuda S, Koizumi K, Shionoya K, Jinushi R, Makazu M, Nishino T, Kimura K, Sumida C, Kubota J, Ichita C, Sasaki A, Kobayashi M, Kako M, Haruki U. Comprehensive review on endoscopic ultrasound-guided tissue acquisition techniques for solid pancreatic tumor. World J Gastroenterol 2023; 29:1863-1874. [PMID: 37032729 PMCID: PMC10080698 DOI: 10.3748/wjg.v29.i12.1863] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 02/02/2023] [Accepted: 03/16/2023] [Indexed: 03/28/2023] Open
Abstract
Pancreatic ductal adenocarcinoma is speculated to become the second leading cause of cancer-related mortality by 2030, a high mortality rate considering the number of cases. Surgery and chemotherapy are the main treatment options, but they are burdensome for patients. A clear histological diagnosis is needed to determine a treatment plan, and endoscopic ultrasound (EUS)-guided tissue acquisition (TA) is a suitable technique that does not worsen the cancer-specific prognosis even for lesions at risk of needle tract seeding. With the development of personalized medicine and precision treatment, there has been an increasing demand to increase cell counts and collect specimens while preserving tissue structure, leading to the development of the fine-needle biopsy (FNB) needle. EUS-FNB is rapidly replacing EUS-guided fine-needle aspiration (FNA) as the procedure of choice for EUS-TA of pancreatic cancer. However, EUS-FNA is sometimes necessary where the FNB needle cannot penetrate small hard lesions, so it is important clinicians are familiar with both. Given these recent dev-elopments, we present an up-to-date review of the role of EUS-TA in pancreatic cancer. Particularly, technical aspects, such as needle caliber, negative pressure, and puncture methods, for obtaining an adequate specimen in EUS-TA are discussed.
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Affiliation(s)
- Sakue Masuda
- Department of Gastroenterology, Shonan Kamakura General Hospital, Kanagawa 247-8533, Japan
| | - Kazuya Koizumi
- Department of Gastroenterology, Shonan Kamakura General Hospital, Kanagawa 247-8533, Japan
| | - Kento Shionoya
- Department of Gastroenterology, Shonan Kamakura General Hospital, Kanagawa 247-8533, Japan
| | - Ryuhei Jinushi
- Department of Gastroenterology, Shonan Kamakura General Hospital, Kanagawa 247-8533, Japan
| | - Makomo Makazu
- Department of Gastroenterology, Shonan Kamakura General Hospital, Kanagawa 247-8533, Japan
| | - Takashi Nishino
- Department of Gastroenterology, Shonan Kamakura General Hospital, Kanagawa 247-8533, Japan
| | - Karen Kimura
- Department of Gastroenterology, Shonan Kamakura General Hospital, Kanagawa 247-8533, Japan
| | - Chihiro Sumida
- Department of Gastroenterology, Shonan Kamakura General Hospital, Kanagawa 247-8533, Japan
| | - Jun Kubota
- Department of Gastroenterology, Shonan Kamakura General Hospital, Kanagawa 247-8533, Japan
| | - Chikamasa Ichita
- Department of Gastroenterology, Shonan Kamakura General Hospital, Kanagawa 247-8533, Japan
| | - Akiko Sasaki
- Department of Gastroenterology, Shonan Kamakura General Hospital, Kanagawa 247-8533, Japan
| | - Masahiro Kobayashi
- Department of Gastroenterology, Shonan Kamakura General Hospital, Kanagawa 247-8533, Japan
| | - Makoto Kako
- Department of Gastroenterology, Shonan Kamakura General Hospital, Kanagawa 247-8533, Japan
| | - Uojima Haruki
- Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, Kanagawa 252-0375, Japan
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Lee YS, Klomp JE, Stalnecker CA, Goodwin CM, Gao Y, Droby GN, Vaziri C, Bryant KL, Der CJ, Cox AD. VCP/p97, a pleiotropic protein regulator of the DNA damage response and proteostasis, is a potential therapeutic target in KRAS-mutant pancreatic cancer. Genes Cancer 2023; 14:30-49. [PMID: 36923647 PMCID: PMC10010283 DOI: 10.18632/genesandcancer.231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Accepted: 02/26/2023] [Indexed: 03/12/2023] Open
Abstract
We and others have recently shown that proteins involved in the DNA damage response (DDR) are critical for KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) cell growth in vitro. However, the CRISPR-Cas9 library that enabled us to identify these key proteins had limited representation of DDR-related genes. To further investigate the DDR in this context, we performed a comprehensive, DDR-focused CRISPR-Cas9 loss-of-function screen. This screen identified valosin-containing protein (VCP) as an essential gene in KRAS-mutant PDAC cell lines. We observed that genetic and pharmacologic inhibition of VCP limited cell growth and induced apoptotic death. Addressing the basis for VCP-dependent growth, we first evaluated the contribution of VCP to the DDR and found that loss of VCP resulted in accumulation of DNA double-strand breaks. We next addressed its role in proteostasis and found that loss of VCP caused accumulation of polyubiquitinated proteins. We also found that loss of VCP increased autophagy. Therefore, we reasoned that inhibiting both VCP and autophagy could be an effective combination. Accordingly, we found that VCP inhibition synergized with the autophagy inhibitor chloroquine. We conclude that concurrent targeting of autophagy can enhance the efficacy of VCP inhibitors in KRAS-mutant PDAC.
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Affiliation(s)
- Ye S. Lee
- Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Jennifer E. Klomp
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Clint A. Stalnecker
- Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Craig M. Goodwin
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Yanzhe Gao
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Gaith N. Droby
- Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Cyrus Vaziri
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Kirsten L. Bryant
- Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Channing J. Der
- Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Adrienne D. Cox
- Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
- Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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Shaya J, Kato S, Adashek JJ, Patel H, Fanta PT, Botta GP, Sicklick JK, Kurzrock R. Personalized matched targeted therapy in advanced pancreatic cancer: a pilot cohort analysis. NPJ Genom Med 2023; 8:1. [PMID: 36670111 PMCID: PMC9860045 DOI: 10.1038/s41525-022-00346-5] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Accepted: 12/07/2022] [Indexed: 01/21/2023] Open
Abstract
Despite progress, 2-year pancreatic cancer survival remains dismal. We evaluated a biomarker-driven, combination/N-of-one strategy in 18 patients (advanced/metastatic pancreatic cancer) (from Molecular Tumor Board). Targeted agents administered/patient = 2.5 (median) (range, 1-4); first-line therapy (N = 5); second line, (N = 13). Comparing patients (high versus low degrees of matching) (matching score ≥50% versus <50%; reflecting number of alterations matched to targeted agents divided by number of pathogenic alterations), survival was significantly longer (hazard ratio [HR] 0.24 (95% confidence interval [CI], 0.078-0.76, P = 0.016); clinical benefit rates (CBR) (stable disease ≥6 months/partial/complete response) trended higher (45.5 vs 0.0%, P = 0.10); progression-free survival, HR, 95% CI, 0.36 (0.12-1.10) (p = 0.075). First versus ≥2nd-line therapy had higher CBRs (80.0 vs 7.7%, P = 0.008). No grade 3-4 toxicities occurred. The longest responder achieved partial remission (17.5 months) by co-targeting MEK and CDK4/6 alterations (chemotherapy-free). Therefore, genomically matched targeted agent combinations were active in these advanced pancreatic cancers. Larger prospective trials are warranted.
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Affiliation(s)
- Justin Shaya
- Division of Hematology and Oncology, Department of Medicine, University of California San Diego Moores Cancer Center, La Jolla, CA, USA
- Center for Personalized Cancer Therapy, University of California San Diego Moores Cancer Center, La Jolla, CA, USA
| | - Shumei Kato
- Division of Hematology and Oncology, Department of Medicine, University of California San Diego Moores Cancer Center, La Jolla, CA, USA.
- Center for Personalized Cancer Therapy, University of California San Diego Moores Cancer Center, La Jolla, CA, USA.
| | - Jacob J Adashek
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at The Johns Hopkins Hospital, Baltimore, MD, USA.
| | - Hitendra Patel
- Division of Hematology and Oncology, Department of Medicine, University of California San Diego Moores Cancer Center, La Jolla, CA, USA
| | - Paul T Fanta
- Division of Hematology and Oncology, Department of Medicine, University of California San Diego Moores Cancer Center, La Jolla, CA, USA
| | - Gregory P Botta
- Division of Hematology and Oncology, Department of Medicine, University of California San Diego Moores Cancer Center, La Jolla, CA, USA
| | - Jason K Sicklick
- Center for Personalized Cancer Therapy, University of California San Diego Moores Cancer Center, La Jolla, CA, USA
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at The Johns Hopkins Hospital, Baltimore, MD, USA
- Department of Surgery, Division of Surgical Oncology, University of California San Diego, UC San Diego Health, San Diego, CA, USA
- Department of Pharmacology, University of California San Diego, UC San Diego Health, San Diego, CA, USA
| | - Razelle Kurzrock
- Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, Milwaukee, WI, USA
- WIN Consortium, Paris, France
- University of Nebraska, Lincoln, NE, USA
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5
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Ji J, Wang C, Fakih M. Targeting KRAS G12C-Mutated Advanced Colorectal Cancer: Research and Clinical Developments. Onco Targets Ther 2022; 15:747-756. [PMID: 35837349 PMCID: PMC9273901 DOI: 10.2147/ott.s340392] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Accepted: 06/24/2022] [Indexed: 12/17/2022] Open
Abstract
Identifying mutations in the KRAS gene has become increasingly important in the treatment of colorectal cancer with many prognostic and therapeutic implications. However, efforts to develop drugs that target KRAS mutations have not been successful until more recently with the introduction of the KRAS G12C inhibitors, sotorasib (AMG510) and adagrasib (MRTX849). Both agents have demonstrated safety and promising efficacy in preclinical studies and early phase trials, but it appears that not all tumor types harboring the KRAS G12C mutation are sensitive to monotherapy approaches. In particular, patients with colorectal cancer (CRC) derive less benefit compared to those with non-small cell lung cancer (NSCLC), likely due to rapid treatment-induced resistance through increased epidermal growth factor receptor (EGFR) signaling. As a result, combination therapy trials with EGFR inhibitors are currently underway. Here, we will review the available clinical trial data on KRASG12C inhibitors in KRAS G12C-mutated CRC, possible mechanisms of resistance to monotherapy, the research studying why available agents are proving to be less efficacious in CRC compared to NSCLC, and future directions for these promising new drugs.
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Affiliation(s)
- Jingran Ji
- Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA, USA
| | - Chongkai Wang
- Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA, USA
| | - Marwan Fakih
- Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA, USA
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6
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Hosein AN, Dougan SK, Aguirre AJ, Maitra A. Translational advances in pancreatic ductal adenocarcinoma therapy. NATURE CANCER 2022; 3:272-286. [PMID: 35352061 DOI: 10.1038/s43018-022-00349-2] [Citation(s) in RCA: 142] [Impact Index Per Article: 47.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Accepted: 02/23/2022] [Indexed: 02/07/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer that is most frequently detected at advanced stages, limiting treatment options to systemic chemotherapy with modest clinical responses. Here, we review recent advances in targeted therapy and immunotherapy for treating subtypes of PDAC with diverse molecular alterations. We focus on the current preclinical and clinical evidence supporting the potential of these approaches and the promise of combinatorial regimens to improve the lives of patients with PDAC.
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Affiliation(s)
- Abdel Nasser Hosein
- Division of Hematology & Oncology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Sheikh Ahmed Bin Zayed Al Nahyan Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Advocate Aurora Health, Vince Lombardi Cancer Clinic, Sheboygan, WI, USA.
| | - Stephanie K Dougan
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA.
- Department of Immunology, Harvard Medical School, Boston, MA, USA.
| | - Andrew J Aguirre
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.
| | - Anirban Maitra
- Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Sheikh Ahmed Bin Zayed Al Nahyan Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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7
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XP-524 is a dual-BET/EP300 inhibitor that represses oncogenic KRAS and potentiates immune checkpoint inhibition in pancreatic cancer. Proc Natl Acad Sci U S A 2022; 119:2116764119. [PMID: 35064087 PMCID: PMC8795568 DOI: 10.1073/pnas.2116764119] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/06/2021] [Indexed: 12/13/2022] Open
Abstract
There are currently no effective treatments for pancreatic ductal adenocarcinoma (PDAC), which displays widespread resistance to chemotherapy, radiation therapy, and immunotherapy. Here, we demonstrate that the multispecificity BET/EP300 inhibitor XP-524 has pronounced single-agent efficacy in vitro, in vivo, and in ex vivo human PDAC slice cultures, functioning in part by attenuating oncogenic KRAS signaling. In vivo XP-524 led to extensive reprogramming of the pancreatic tumor microenvironment, sensitizing murine carcinoma to immune checkpoint inhibition and further extending survival. Given the urgent need for therapeutic approaches in PDAC, the combination of XP-524 and immune checkpoint inhibition warrants additional exploration. Pancreatic ductal adenocarcinoma (PDAC) is associated with extensive dysregulation of the epigenome and epigenetic regulators, such as bromodomain and extraterminal motif (BET) proteins, have been suggested as potential targets for therapy. However, single-agent BET inhibition has shown poor efficacy in clinical trials, and no epigenetic approaches are currently used in PDAC. To circumvent the limitations of the current generation of BET inhibitors, we developed the compound XP-524 as an inhibitor of the BET protein BRD4 and the histone acetyltransferase EP300/CBP, both of which are ubiquitously expressed in PDAC tissues and cooperate to enhance tumorigenesis. XP-524 showed increased potency and superior tumoricidal activity than the benchmark BET inhibitor JQ-1 in vitro, with comparable efficacy to higher-dose JQ-1 combined with the EP300/CBP inhibitor SGC-CBP30. We determined that this is in part due to the epigenetic silencing of KRAS in vitro, with similar results observed using ex vivo slice cultures of human PDAC tumors. Accordingly, XP-524 prevented KRAS-induced, neoplastic transformation in vivo and extended survival in two transgenic mouse models of aggressive PDAC. In addition to the inhibition of KRAS/MAPK signaling, XP-524 also enhanced the presentation of self-peptide and tumor recruitment of cytotoxic T lymphocytes, though these lymphocytes remained refractory from full activation. We, therefore, combined XP-524 with an anti–PD-1 antibody in vivo, which reactivated the cytotoxic immune program and extended survival well beyond XP-524 in monotherapy. Pending a comprehensive safety evaluation, these results suggest that XP-524 may benefit PDAC patients and warrant further exploration, particularly in combination with immune checkpoint inhibition.
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8
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Lundy J, Harris M, Zalcberg J, Zimet A, Goldstein D, Gebski V, Borsaru A, Desmond C, Swan M, Jenkins BJ, Croagh D. EUS-FNA Biopsies to Guide Precision Medicine in Pancreatic Cancer: Results of a Pilot Study to Identify KRAS Wild-Type Tumours for Targeted Therapy. Front Oncol 2021; 11:770022. [PMID: 34956889 PMCID: PMC8696205 DOI: 10.3389/fonc.2021.770022] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 11/18/2021] [Indexed: 12/27/2022] Open
Abstract
Background Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer death and lacks effective treatment options. Diagnostic endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) biopsies represent an appealing source of material for molecular analysis to inform targeted therapy, as they are often the only available tissue for patients presenting with PDAC irrespective of disease stage. However, EUS-FNA biopsies are typically not used to screen for precision medicine studies due to concerns about low tissue yield and quality. Epidermal growth factor receptor (EGFR) inhibition has shown promise in clinical trials of unselected patients with advanced pancreatic cancer, but has not been prospectively tested in KRAS wild-type patients. Here, we examine the clinical utility of EUS-FNA biopsies for molecular screening of KRAS wild-type PDAC patients for targeted anti-EGFR therapy to assess the feasibility of this approach. Patients and Methods Fresh frozen EUS-FNA or surgical biopsies from PDAC patient tumours were used to screen for KRAS mutations. Eligible patients with recurrent, locally advanced, or metastatic KRAS wild-type status who had received at least one prior line of chemotherapy were enrolled in a pilot study (ACTRN12617000540314) and treated with panitumumab at 6mg/kg intravenously every 2 weeks until progression or unacceptable toxicity. The primary endpoint was 4-month progression-free survival (PFS). Results 275 patient biopsies were screened for KRAS mutations, which were detected in 88.3% of patient samples. 8 eligible KRAS wild-type patients were enrolled onto the interventional study between November 2017 and December 2020 and treated with panitumumab. 4-month PFS was 14.3% with no objective tumour responses observed. The only grade 3/4 treatment related toxicity observed was hypomagnesaemia. Conclusions This study demonstrates proof-of-principle feasibility to molecularly screen patients with pancreatic cancer for targeted therapies, and confirms diagnostic EUS-FNA biopsies as a reliable source of tumour material for molecular analysis. Single agent panitumumab was safe and tolerable but led to no objective tumour responses in this population.
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Affiliation(s)
- Joanne Lundy
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia.,Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC, Australia.,Department of Surgery, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC, Australia
| | - Marion Harris
- Department of Oncology, Faculty of Medicine, Nursing and Health Sciences and School of Clinical Sciences, Monash University, Clayton, VIC, Australia
| | - John Zalcberg
- Department of Medical Oncology, Alfred Health, Melbourne, VIC, Australia.,Public Health and Preventative Medicine, Monash University, Melbourne, VIC, Australia
| | - Allan Zimet
- Department of Medical Oncology, Epworth Hospital, Melbourne, VIC, Australia
| | - David Goldstein
- Prince of Wales Clinical School, University of New South Wales, Sydney, NSW, Australia.,Department of Medical Oncology, Prince of Wales Hospital, Randwick, NSW, Australia
| | - Val Gebski
- National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Camperdown, NSW, Australia
| | - Adina Borsaru
- Diagnostic Imaging, Monash Health, Melbourne, VIC, Australia
| | | | - Michael Swan
- Department of Gastroenterology, Monash Health, Melbourne, VIC, Australia
| | - Brendan J Jenkins
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia.,Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC, Australia
| | - Daniel Croagh
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia.,Department of Surgery, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC, Australia.,Department of Surgery, Epworth Healthcare, Melbourne, VIC, Australia
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9
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Alawawdeh A, Price T, Karapetis C, Piantadosi C, Padbury R, Roy A, Maddern G, Moore J, Carruthers S, Roder D, Townsend AR. Regorafenib outcomes from the population based South Australian Metastatic Colorectal Cancer Registry. Asia Pac J Clin Oncol 2021; 18:428-433. [PMID: 34811937 DOI: 10.1111/ajco.13672] [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: 06/29/2021] [Accepted: 08/17/2021] [Indexed: 11/28/2022]
Abstract
AIM Reviewing outcomes of regorafenib use in metastatic colorectal cancer using real-world data from the South Australian Metastatic Colorectal Cancer Registry. METHODS A retrospective review of the characteristics and outcomes of patients who received regorafenib in the Registry up to December 2018. The registry started in February 2006. RESULTS Fifty-three patients received regorafenib therapy since approved by the therapeutic goods administration in November 2013. The median age was 66 (range 34-82). 66% were male, 66% had stage IV disease at diagnosis, 53% had liver only involvement, whereas 13% had liver and lung disease and 6% had lung only involvement. 75% had left-sided primary. KRAS was available in 35/53 patients with 49% of them being WT. BRAF status was known in 8/53 with 25% of them having a mutated variant. MSI testing was known in 14 patients in whom 21% of them had MSI-High tumors. Prior lines of treatment received: one line 4%, two 9%, three 23%, four 26%, >four 37%. Prior biological use: bevacizumab 72%, anti-EGFR 100% (for RAS WT). Median survival from diagnosis was 3.3 years (95% CI, 2.8-3.8 years). Median survival from the start of regorafenib was 7.1 months (95% CI, 4.8-9.4 months) and the 12-month survival rate was 28%. CONCLUSION The survival outcome for those patients from our population-based registry who access regorafenib is in keeping with reports from large, randomized trials. Thus, clinicians can quote local real world data when discussing efficacy and access to regorafenib therapy for mCRC patients.
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Affiliation(s)
- Anas Alawawdeh
- Department of Medical Oncology, The Queen Elizabeth Hospital and University of Adelaide, Adelaide, SA, Australia
| | - Timothy Price
- Department of Medical Oncology, The Queen Elizabeth Hospital and University of Adelaide, Adelaide, SA, Australia
| | - Christos Karapetis
- Department of Medical Oncology, Flinders Medical Centre and Flinders University, Adelaide, SA, Australia
| | - Cynthia Piantadosi
- Department of Surgery, Flinders Medical Centre, Bedford Park, SA, Australia
| | - Rob Padbury
- Department of Surgery, Flinders Medical Centre, Bedford Park, SA, Australia
| | - Amitesh Roy
- Department of Medical Oncology, Flinders Medical Centre and Flinders University, Adelaide, SA, Australia
| | - Guy Maddern
- Department of Surgery, The Queen Elizabeth Hospital, Adelaide, SA, Australia.,Department of Surgery, University of Adelaide, Adelaide, SA, Australia
| | - James Moore
- Department of Surgery, Royal Adelaide Hospital, Adelaide, SA, Australia
| | | | - David Roder
- Department of Epidemiology, University of South Australia, Adelaide, SA, Australia
| | - Amanda R Townsend
- Department of Medical Oncology, The Queen Elizabeth Hospital and University of Adelaide, Adelaide, SA, Australia
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10
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Baldelli E, El Gazzah E, Moran JC, Hodge KA, Manojlovic Z, Bassiouni R, Carpten JD, Ludovini V, Baglivo S, Crinò L, Bianconi F, Dong T, Loffredo J, Petricoin EF, Pierobon M. Wild-Type KRAS Allele Effects on Druggable Targets in KRAS Mutant Lung Adenocarcinomas. Genes (Basel) 2021; 12:genes12091402. [PMID: 34573384 PMCID: PMC8467269 DOI: 10.3390/genes12091402] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 09/04/2021] [Accepted: 09/08/2021] [Indexed: 11/16/2022] Open
Abstract
KRAS mutations are one of the most common oncogenic drivers in non-small cell lung cancer (NSCLC) and in lung adenocarcinomas in particular. Development of therapeutics targeting KRAS has been incredibly challenging, prompting indirect inhibition of downstream targets such as MEK and ERK. Such inhibitors, unfortunately, come with limited clinical efficacy, and therefore the demand for developing novel therapeutic strategies remains an urgent need for these patients. Exploring the influence of wild-type (WT) KRAS on druggable targets can uncover new vulnerabilities for the treatment of KRAS mutant lung adenocarcinomas. Using commercially available KRAS mutant lung adenocarcinoma cell lines, we explored the influence of WT KRAS on signaling networks and druggable targets. Expression and/or activation of 183 signaling proteins, most of which are targets of FDA-approved drugs, were captured by reverse-phase protein microarray (RPPA). Selected findings were validated on a cohort of 23 surgical biospecimens using the RPPA. Kinase-driven signatures associated with the presence of the KRAS WT allele were detected along the MAPK and AKT/mTOR signaling pathway and alterations of cell cycle regulators. FoxM1 emerged as a potential vulnerability of tumors retaining the KRAS WT allele both in cell lines and in the clinical samples. Our findings suggest that loss of WT KRAS impacts on signaling events and druggable targets in KRAS mutant lung adenocarcinomas.
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Affiliation(s)
- Elisa Baldelli
- Center for Applied Proteomics & Molecular Medicine, George Mason University, Manassas, VA 20110, USA; (E.B.); (E.E.G.); (J.C.M.); (K.A.H.); (T.D.); (J.L.); (E.F.P.)
| | - Emna El Gazzah
- Center for Applied Proteomics & Molecular Medicine, George Mason University, Manassas, VA 20110, USA; (E.B.); (E.E.G.); (J.C.M.); (K.A.H.); (T.D.); (J.L.); (E.F.P.)
- School of Systems Biology, George Mason University, Manassas, VA 20110, USA
| | - John Conor Moran
- Center for Applied Proteomics & Molecular Medicine, George Mason University, Manassas, VA 20110, USA; (E.B.); (E.E.G.); (J.C.M.); (K.A.H.); (T.D.); (J.L.); (E.F.P.)
| | - Kimberley A. Hodge
- Center for Applied Proteomics & Molecular Medicine, George Mason University, Manassas, VA 20110, USA; (E.B.); (E.E.G.); (J.C.M.); (K.A.H.); (T.D.); (J.L.); (E.F.P.)
| | - Zarko Manojlovic
- Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; (Z.M.); (R.B.); (J.D.C.)
| | - Rania Bassiouni
- Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; (Z.M.); (R.B.); (J.D.C.)
| | - John D. Carpten
- Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; (Z.M.); (R.B.); (J.D.C.)
| | - Vienna Ludovini
- Division of Medical Oncology, S. Maria della Misericordia Hospital, 06156 Perugia, Italy; (V.L.); (S.B.)
| | - Sara Baglivo
- Division of Medical Oncology, S. Maria della Misericordia Hospital, 06156 Perugia, Italy; (V.L.); (S.B.)
| | - Lucio Crinò
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy;
| | | | - Ting Dong
- Center for Applied Proteomics & Molecular Medicine, George Mason University, Manassas, VA 20110, USA; (E.B.); (E.E.G.); (J.C.M.); (K.A.H.); (T.D.); (J.L.); (E.F.P.)
| | - Jeremy Loffredo
- Center for Applied Proteomics & Molecular Medicine, George Mason University, Manassas, VA 20110, USA; (E.B.); (E.E.G.); (J.C.M.); (K.A.H.); (T.D.); (J.L.); (E.F.P.)
| | - Emanuel F. Petricoin
- Center for Applied Proteomics & Molecular Medicine, George Mason University, Manassas, VA 20110, USA; (E.B.); (E.E.G.); (J.C.M.); (K.A.H.); (T.D.); (J.L.); (E.F.P.)
| | - Mariaelena Pierobon
- Center for Applied Proteomics & Molecular Medicine, George Mason University, Manassas, VA 20110, USA; (E.B.); (E.E.G.); (J.C.M.); (K.A.H.); (T.D.); (J.L.); (E.F.P.)
- School of Systems Biology, George Mason University, Manassas, VA 20110, USA
- Correspondence: ; Tel.: +1-703-993-9839
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11
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Beatty GL, Werba G, Lyssiotis CA, Simeone DM. The biological underpinnings of therapeutic resistance in pancreatic cancer. Genes Dev 2021; 35:940-962. [PMID: 34117095 PMCID: PMC8247606 DOI: 10.1101/gad.348523.121] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related mortality in the United States and has only recently achieved a 5-yr survival rate of 10%. This dismal prognosis reflects the remarkable capacity of PDAC to effectively adapt to and resist therapeutic intervention. In this review, we discuss recent advances in our understanding of the biological underpinnings of PDAC and their implications as targetable vulnerabilities in this highly lethal disease.
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Affiliation(s)
- Gregory L Beatty
- Abramson Cancer Center; University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
- Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
| | - Gregor Werba
- Department of Surgery, New York University School of Medicine, New York, New York 10016, USA
- Perlmutter Cancer Center, New York University Langone Medical Center, New York, New York 10016, USA
| | - Costas A Lyssiotis
- Department of Molecular and Integrative Physiology, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan 48109, USA
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan 48109, USA
- Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, USA
| | - Diane M Simeone
- Department of Surgery, New York University School of Medicine, New York, New York 10016, USA
- Perlmutter Cancer Center, New York University Langone Medical Center, New York, New York 10016, USA
- Department of Pathology, New York University School of Medicine, New York, New York 10016, USA
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12
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Roosan MR, Mambetsariev I, Pharaon R, Fricke J, Baroz AR, Chao J, Chen C, Nasser MW, Chirravuri-Venkata R, Jain M, Smith L, Yost SE, Reckamp KL, Pillai R, Arvanitis L, Afkhami M, Wang EW, Chung V, Cristea M, Fakih M, Koczywas M, Massarelli E, Mortimer J, Yuan Y, Batra SK, Pal S, Salgia R. Evaluation of Somatic Mutations in Solid Metastatic Pan-Cancer Patients. Cancers (Basel) 2021; 13:2776. [PMID: 34204917 PMCID: PMC8199748 DOI: 10.3390/cancers13112776] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 05/27/2021] [Accepted: 05/28/2021] [Indexed: 12/12/2022] Open
Abstract
Metastasis continues to be the primary cause of all cancer-related deaths despite the recent advancements in cancer treatments. To evaluate the role of mutations in overall survival (OS) and treatment outcomes, we analyzed 957 metastatic patients with seven major cancer types who had available molecular testing results with a FoundationOne CDx® panel. The most prevalent genes with somatic mutations were TP53, KRAS, APC, and LRP1B. In this analysis, these genes had mutation frequencies higher than in publicly available datasets. We identified that the somatic mutations were seven mutually exclusive gene pairs and an additional fifty-two co-occurring gene pairs. Mutations in the mutually exclusive gene pair APC and CDKN2A showed an opposite effect on the overall survival. However, patients with CDKN2A mutations showed significantly shorter OS (HR: 1.72, 95% CI: 1.34-2.21, p < 0.001) after adjusting for cancer type, age at diagnosis, and sex. Five-year post metastatic diagnosis survival analysis showed a significant improvement in OS (median survival 28 and 43 months in pre-2015 and post-2015 metastatic diagnosis, respectively, p = 0.00021) based on the year of metastatic diagnosis. Although the use of targeted therapies after metastatic diagnosis prolonged OS, the benefit was not statistically significant. However, longer five-year progression-free survival (PFS) was significantly associated with targeted therapy use (median 10.9 months (CI: 9.7-11.9 months) compared to 9.1 months (CI: 8.1-10.1 months) for non-targeted therapy, respectively, p = 0.0029). Our results provide a clinically relevant overview of the complex molecular landscape and survival mechanisms in metastatic solid cancers.
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Affiliation(s)
- Moom R. Roosan
- School of Pharmacy, Chapman University, Irvine, CA 92618, USA;
| | - Isa Mambetsariev
- Department of Medical Oncology & Therapeutics Research, City of Hope, Duarte, CA 91010, USA; (I.M.); (R.P.); (J.F.); (A.R.B.); (J.C.); (S.E.Y.); (K.L.R.); (E.W.W.); (V.C.); (M.C.); (M.F.); (M.K.); (E.M.); (J.M.); (Y.Y.)
| | - Rebecca Pharaon
- Department of Medical Oncology & Therapeutics Research, City of Hope, Duarte, CA 91010, USA; (I.M.); (R.P.); (J.F.); (A.R.B.); (J.C.); (S.E.Y.); (K.L.R.); (E.W.W.); (V.C.); (M.C.); (M.F.); (M.K.); (E.M.); (J.M.); (Y.Y.)
| | - Jeremy Fricke
- Department of Medical Oncology & Therapeutics Research, City of Hope, Duarte, CA 91010, USA; (I.M.); (R.P.); (J.F.); (A.R.B.); (J.C.); (S.E.Y.); (K.L.R.); (E.W.W.); (V.C.); (M.C.); (M.F.); (M.K.); (E.M.); (J.M.); (Y.Y.)
| | - Angel R. Baroz
- Department of Medical Oncology & Therapeutics Research, City of Hope, Duarte, CA 91010, USA; (I.M.); (R.P.); (J.F.); (A.R.B.); (J.C.); (S.E.Y.); (K.L.R.); (E.W.W.); (V.C.); (M.C.); (M.F.); (M.K.); (E.M.); (J.M.); (Y.Y.)
| | - Joseph Chao
- Department of Medical Oncology & Therapeutics Research, City of Hope, Duarte, CA 91010, USA; (I.M.); (R.P.); (J.F.); (A.R.B.); (J.C.); (S.E.Y.); (K.L.R.); (E.W.W.); (V.C.); (M.C.); (M.F.); (M.K.); (E.M.); (J.M.); (Y.Y.)
| | - Chen Chen
- Applied AI and Data Science, City of Hope, Duarte, CA 91010, USA;
| | - Mohd W. Nasser
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA; (M.W.N.); (R.C.-V.); (M.J.); (S.K.B.)
| | - Ramakanth Chirravuri-Venkata
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA; (M.W.N.); (R.C.-V.); (M.J.); (S.K.B.)
| | - Maneesh Jain
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA; (M.W.N.); (R.C.-V.); (M.J.); (S.K.B.)
| | - Lynette Smith
- Department of Biostatistics, University of Nebraska Medical Center, Omaha, NE 68198, USA;
| | - Susan E. Yost
- Department of Medical Oncology & Therapeutics Research, City of Hope, Duarte, CA 91010, USA; (I.M.); (R.P.); (J.F.); (A.R.B.); (J.C.); (S.E.Y.); (K.L.R.); (E.W.W.); (V.C.); (M.C.); (M.F.); (M.K.); (E.M.); (J.M.); (Y.Y.)
| | - Karen L. Reckamp
- Department of Medical Oncology & Therapeutics Research, City of Hope, Duarte, CA 91010, USA; (I.M.); (R.P.); (J.F.); (A.R.B.); (J.C.); (S.E.Y.); (K.L.R.); (E.W.W.); (V.C.); (M.C.); (M.F.); (M.K.); (E.M.); (J.M.); (Y.Y.)
- Cedars-Sinai Medical Center, Department of Medicine, Division of Medical Oncology, Los Angeles, CA 90048, USA
| | - Raju Pillai
- Department of Pathology, City of Hope, Duarte, CA 91010, USA; (R.P.); (L.A.); (M.A.)
| | - Leonidas Arvanitis
- Department of Pathology, City of Hope, Duarte, CA 91010, USA; (R.P.); (L.A.); (M.A.)
| | - Michelle Afkhami
- Department of Pathology, City of Hope, Duarte, CA 91010, USA; (R.P.); (L.A.); (M.A.)
| | - Edward W. Wang
- Department of Medical Oncology & Therapeutics Research, City of Hope, Duarte, CA 91010, USA; (I.M.); (R.P.); (J.F.); (A.R.B.); (J.C.); (S.E.Y.); (K.L.R.); (E.W.W.); (V.C.); (M.C.); (M.F.); (M.K.); (E.M.); (J.M.); (Y.Y.)
| | - Vincent Chung
- Department of Medical Oncology & Therapeutics Research, City of Hope, Duarte, CA 91010, USA; (I.M.); (R.P.); (J.F.); (A.R.B.); (J.C.); (S.E.Y.); (K.L.R.); (E.W.W.); (V.C.); (M.C.); (M.F.); (M.K.); (E.M.); (J.M.); (Y.Y.)
| | - Mihaela Cristea
- Department of Medical Oncology & Therapeutics Research, City of Hope, Duarte, CA 91010, USA; (I.M.); (R.P.); (J.F.); (A.R.B.); (J.C.); (S.E.Y.); (K.L.R.); (E.W.W.); (V.C.); (M.C.); (M.F.); (M.K.); (E.M.); (J.M.); (Y.Y.)
| | - Marwan Fakih
- Department of Medical Oncology & Therapeutics Research, City of Hope, Duarte, CA 91010, USA; (I.M.); (R.P.); (J.F.); (A.R.B.); (J.C.); (S.E.Y.); (K.L.R.); (E.W.W.); (V.C.); (M.C.); (M.F.); (M.K.); (E.M.); (J.M.); (Y.Y.)
| | - Marianna Koczywas
- Department of Medical Oncology & Therapeutics Research, City of Hope, Duarte, CA 91010, USA; (I.M.); (R.P.); (J.F.); (A.R.B.); (J.C.); (S.E.Y.); (K.L.R.); (E.W.W.); (V.C.); (M.C.); (M.F.); (M.K.); (E.M.); (J.M.); (Y.Y.)
| | - Erminia Massarelli
- Department of Medical Oncology & Therapeutics Research, City of Hope, Duarte, CA 91010, USA; (I.M.); (R.P.); (J.F.); (A.R.B.); (J.C.); (S.E.Y.); (K.L.R.); (E.W.W.); (V.C.); (M.C.); (M.F.); (M.K.); (E.M.); (J.M.); (Y.Y.)
| | - Joanne Mortimer
- Department of Medical Oncology & Therapeutics Research, City of Hope, Duarte, CA 91010, USA; (I.M.); (R.P.); (J.F.); (A.R.B.); (J.C.); (S.E.Y.); (K.L.R.); (E.W.W.); (V.C.); (M.C.); (M.F.); (M.K.); (E.M.); (J.M.); (Y.Y.)
| | - Yuan Yuan
- Department of Medical Oncology & Therapeutics Research, City of Hope, Duarte, CA 91010, USA; (I.M.); (R.P.); (J.F.); (A.R.B.); (J.C.); (S.E.Y.); (K.L.R.); (E.W.W.); (V.C.); (M.C.); (M.F.); (M.K.); (E.M.); (J.M.); (Y.Y.)
| | - Surinder K. Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA; (M.W.N.); (R.C.-V.); (M.J.); (S.K.B.)
| | - Sumanta Pal
- Department of Medical Oncology & Therapeutics Research, City of Hope, Duarte, CA 91010, USA; (I.M.); (R.P.); (J.F.); (A.R.B.); (J.C.); (S.E.Y.); (K.L.R.); (E.W.W.); (V.C.); (M.C.); (M.F.); (M.K.); (E.M.); (J.M.); (Y.Y.)
| | - Ravi Salgia
- Department of Medical Oncology & Therapeutics Research, City of Hope, Duarte, CA 91010, USA; (I.M.); (R.P.); (J.F.); (A.R.B.); (J.C.); (S.E.Y.); (K.L.R.); (E.W.W.); (V.C.); (M.C.); (M.F.); (M.K.); (E.M.); (J.M.); (Y.Y.)
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Abstract
PURPOSE OF REVIEW Mutations in kirsten rat sarcoma viral oncogene homolog (KRAS) are the most frequently observed genomic alterations in human cancers. No KRAS targeting therapy has been approved despite more than three decades of efforts. Encouraging progress has been made in targeting KRASG12C with KRASG12C specific covalent inhibitors in the past few years. Herein, we review the recent breakthroughs in KRAS targeting. RECENT FINDINGS KRASG12C mutation was found in 14% of non-small cell lung cancer (NSCLC) and 3% of colorectal cancer. Recently, highly potent KRASG12C specific inhibitors have been developed and demonstrated potent activity in preclinical models. Early results from phase 1 clinical trials with sotorasib and MRTX849 show promising antitumor activity in NSCLC, colorectal cancer and other solid tumors harboring KRASG12C mutation. For the first time, the preclinical success of targeting KRAS has translated into clinical benefits, which holds the potential of transforming clinical management of KRAS mutated solid tumors. Additional efforts are needed to identify biomarkers that predict response to KRAS inhibition in patients with KRASG12C as well as to develop strategies to overcome resistance.
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Affiliation(s)
- Chongkai Wang
- Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, 1500 E Duarte Rd, Duarte, CA, 91010, USA
| | - Marwan Fakih
- Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, 1500 E Duarte Rd, Duarte, CA, 91010, USA.
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14
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Zheng-Lin B, O'Reilly EM. Pancreatic ductal adenocarcinoma in the era of precision medicine. Semin Oncol 2021; 48:19-33. [PMID: 33637355 PMCID: PMC8355264 DOI: 10.1053/j.seminoncol.2021.01.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Accepted: 01/21/2021] [Indexed: 12/13/2022]
Abstract
The paradigm for treatment of PDAC is shifting from a "one size fits all" of cytotoxic therapy to a precision medicine approach based on specific predictive biomarkers for a subset of patients. As the genomic landscape of pancreatic carcinogenesis has become increasingly defined, several oncogenic alterations have emerged as actionable targets and their use has been validated in novel approaches such as targeting mutated germline DNA damage response genes (BRCA) and mismatch deficiency (dMMR/MSI-H) or blockade of rare somatic oncogenic fusions. Chemotherapy selection based on transcriptomic subtypes and developing stroma- and immune-modulating strategies have yielded encouraging results and may open therapeutic refinement to a broader PDAC population. Notwithstanding, a series of negative late-stage trials over the last year continue to underscore the inherent challenges in the treatment of PDAC. Multifactorial therapy resistance warrants further exploration in PDAC "omics" and tumor-stroma-immune cells crosstalk. Herein, we discuss precision medicine approaches applied to the treatment of PDAC, its current state and future perspective.
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Affiliation(s)
- Binbin Zheng-Lin
- Department of Medicine, Icahn School of Medicine at Mount Sinai Morningside and Mount Sinai West, New York, NY, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Eileen M O'Reilly
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Department of Medicine, Weill Cornell Medicine, New York, NY, USA; David M. Rubenstein Center for Pancreatic Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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15
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Batra U, Nathany S, Diwan H. Batra et al.'s reply to Ventrapati and Gheware et al. CANCER RESEARCH, STATISTICS, AND TREATMENT 2021. [DOI: 10.4103/crst.crst_276_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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16
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Ventrapati P. Old targets, new bullets, nursing fresh hope. CANCER RESEARCH, STATISTICS, AND TREATMENT 2021. [DOI: 10.4103/crst.crst_250_21] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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17
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van Brummelen EMJ, Huijberts S, van Herpen C, Desar I, Opdam F, van Geel R, Marchetti S, Steeghs N, Monkhorst K, Thijssen B, Rosing H, Huitema A, Beijnen J, Bernards R, Schellens J. Phase I Study of Afatinib and Selumetinib in Patients with KRAS-Mutated Colorectal, Non-Small Cell Lung, and Pancreatic Cancer. Oncologist 2020; 26:290-e545. [PMID: 33296125 DOI: 10.1002/onco.13631] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2020] [Accepted: 11/30/2020] [Indexed: 01/21/2023] Open
Abstract
LESSONS LEARNED Afatinib and selumetinib can be combined in continuous and intermittent dosing schedules, albeit at lower doses than approved for monotherapy. Maximum tolerated dose for continuous and intermittent schedules is afatinib 20 mg once daily and selumetinib 25 mg b.i.d. Because the anticancer activity was limited, further development of this combination is not recommended until better biomarkers for response and resistance are defined. BACKGROUND Antitumor effects of MEK inhibitors are limited in KRAS-mutated tumors because of feedback activation of upstream epidermal growth factor receptors, which reactivates the MAPK and the phosphoinositide 3-kinase-AKT pathway. Therefore, this phase I trial was initiated with the pan-HER inhibitor afatinib plus the MEK inhibitor selumetinib in patients with KRAS mutant, PIK3CA wild-type tumors. METHODS Afatinib and selumetinib were administered according to a 3+3 design in continuous and intermittent schedules. The primary objective was safety, and the secondary objective was clinical efficacy. RESULTS Twenty-six patients were enrolled with colorectal cancer (n = 19), non-small cell lung cancer (NSCLC) (n = 6), and pancreatic cancer (n = 1). Dose-limiting toxicities occurred in six patients, including grade 3 diarrhea, dehydration, decreased appetite, nausea, vomiting, and mucositis. The recommended phase II dose (RP2D) was 20 mg afatinib once daily (QD) and 25 mg selumetinib b.i.d. (21 days on/7 days off) for continuous afatinib dosing and for intermittent dosing with both drugs 5 days on/2 days off. Efficacy was limited with disease stabilization for 221 days in a patient with NSCLC as best response. CONCLUSION Afatinib and selumetinib can be combined in continuous and intermittent schedules in patients with KRAS mutant tumors. Although target engagement was observed, the clinical efficacy was limited.
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Affiliation(s)
- Emilie M J van Brummelen
- Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Sanne Huijberts
- Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Carla van Herpen
- Department of Medical Oncology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Ingrid Desar
- Department of Medical Oncology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Frans Opdam
- Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Robin van Geel
- Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.,Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Serena Marchetti
- Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Neeltje Steeghs
- Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Kim Monkhorst
- Department of Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Bas Thijssen
- Department of Pharmacy, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Hilde Rosing
- Department of Pharmacy, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Alwin Huitema
- Department of Pharmacy, The Netherlands Cancer Institute, Amsterdam, The Netherlands.,Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Jos Beijnen
- Department of Pharmacy, The Netherlands Cancer Institute, Amsterdam, The Netherlands.,Utrecht University, Utrecht, The Netherlands
| | - Rene Bernards
- Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, The Netherlands.,Utrecht University, Utrecht, The Netherlands
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18
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Sreedurgalakshmi K, Srikar R, Rajkumari R. CRISPR-Cas deployment in non-small cell lung cancer for target screening, validations, and discoveries. Cancer Gene Ther 2020; 28:566-580. [PMID: 33191402 DOI: 10.1038/s41417-020-00256-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 10/14/2020] [Accepted: 10/29/2020] [Indexed: 12/24/2022]
Abstract
Continued advancements in CRISPR-Cas systems have accelerated genome research. Use of CRISPR-Cas in cancer research has been of great interest that is resulting in development of orthogonal methods for drug target validations and discovery of new therapeutic targets through genome-wide screens of cancer cells. CRISPR-based screens have also revealed several new cancer drivers through alterations in tumor suppressor genes (TSGs) and oncogenes inducing resistance to targeted therapies via activation of alternate signaling pathways. Given such dynamic status of cancer, we review the application of CRISPR-Cas in non-small cell lung cancer (NSCLC) for development of mutant models, drug screening, target validation, novel target discoveries, and other emerging potential applications. In addition, CRISPR-based approach for development of novel anticancer combination therapies is also discussed in this review.
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Affiliation(s)
- K Sreedurgalakshmi
- School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamilnadu, India.,Division of Biosimilars and Gene Therapy, R&D, Levim Biotech LLP, Chennai, Tamilnadu, India
| | - R Srikar
- Division of Biosimilars and Gene Therapy, R&D, Levim Biotech LLP, Chennai, Tamilnadu, India.
| | - Reena Rajkumari
- School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamilnadu, India.
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Wang Y, Lakoma A, Zogopoulos G. Building towards Precision Oncology for Pancreatic Cancer: Real-World Challenges and Opportunities. Genes (Basel) 2020; 11:E1098. [PMID: 32967105 PMCID: PMC7563487 DOI: 10.3390/genes11091098] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2020] [Revised: 09/15/2020] [Accepted: 09/17/2020] [Indexed: 02/06/2023] Open
Abstract
The advent of next-generation sequencing (NGS) has provided unprecedented insight into the molecular complexity of pancreatic ductal adenocarcinoma (PDAC). This has led to the emergence of biomarker-driven treatment paradigms that challenge empiric treatment approaches. However, the growth of sequencing technologies is outpacing the development of the infrastructure required to implement precision oncology as routine clinical practice. Addressing these logistical barriers is imperative to maximize the clinical impact of molecular profiling initiatives. In this review, we examine the evolution of precision oncology in PDAC, spanning from germline testing for cancer susceptibility genes to multi-omic tumor profiling. Furthermore, we highlight real-world challenges to delivering precision oncology for PDAC, and propose strategies to improve the generation, interpretation, and clinical translation of molecular profiling data.
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Affiliation(s)
- Yifan Wang
- Department of Surgery, McGill University, Montreal, QC H4A 3J1, Canada; (Y.W.); (A.L.)
- Research Institute of the McGill University Health Centre, McGill University, Montreal, QC H4A 3J1, Canada
- The Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada
| | - Anna Lakoma
- Department of Surgery, McGill University, Montreal, QC H4A 3J1, Canada; (Y.W.); (A.L.)
- Research Institute of the McGill University Health Centre, McGill University, Montreal, QC H4A 3J1, Canada
- The Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada
| | - George Zogopoulos
- Department of Surgery, McGill University, Montreal, QC H4A 3J1, Canada; (Y.W.); (A.L.)
- Research Institute of the McGill University Health Centre, McGill University, Montreal, QC H4A 3J1, Canada
- The Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada
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