Abstract
Introduction: Approximately 4% of NSCLC harbor BRAF mutations, and approximately 50% of these are non-V600 mutations. Treatment of tumors harboring non-V600 mutations is challenging because of functional heterogeneity and lack of knowledge regarding their clinical significance and response to targeted agents. Methods: We conducted an integrative analysis of BRAF non-V600 mutations using genomic profiles of BRAF-mutant NSCLC from the Guardant360 database. BRAF mutations were categorized by clonality and class (1 and 2: RAS-independent; 3: RAS-dependent). Cell viability assays were performed in Ba/F3 models. Drug screens were performed in NSCLC cell lines. Results: A total of 305 unique BRAF mutations were identified. Missense mutations were most common (276, 90%), and 45% were variants of unknown significance. F468S and N581Y were identified as novel activating mutations. Class 1 to 3 mutations had higher clonality than mutations of unknown class (p < 0.01). Three patients were treated with MEK with or without BRAF inhibitors. Patients harboring G469V and D594G mutations did not respond, whereas a patient with the L597R mutation had a durable response. Trametinib with or without dabrafenib, LXH254, and lifirafenib had more potent inhibition of BRAF non–V600-mutant NSCLC cell lines than other MEK, BRAF, and ERK inhibitors, comparable with the inhibition of BRAF V600E cell line. Conclusions: In BRAF-mutant NSCLC, clonality is higher in known functional mutations and may allow identification of variants of unknown significance that are more likely to be oncogenic drivers. Our data indicate that certain non-V600 mutations are responsive to MEK and BRAF inhibitors. This integration of genomic profiling and drug sensitivity may guide the treatment for BRAF-mutant NSCLC.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1611-1623 |
| Number of pages | 13 |
| Journal | Journal of Thoracic Oncology |
| Volume | 15 |
| Issue number | 10 |
| DOIs | |
| State | Published - Oct 2020 |
Funding
Disclosure: Ms. Raymond was (and is) an employee and a shareholder at Guardant Health during the conduct of the study. Dr. Lanman reports personal fees from Guardant Health, Inc., during the conduct of the study. Dr. Robichaux reports royalties from a licensed patent on EGFR/HER2 exon 20 from Spectrum Pharmaceuticals outside of the submitted work. Dr. Nilsson reports royalties from a licensed patent on EGFR/HER2 exon 20 from Spectrum Pharmaceuticals outside of the submitted work. Nagy was (and is) an employee and shareholder at Guardant Health during the conduct of the study. Ms. Banks reports personal fees from Guardant Health during the conduct of the study. Dr. Zhu reports other fees from AstraZeneca, Roche-Foundation Medicine, Roche/Genentech, Takeda, and TP Therapeutics outside of the submitted work. Dr. Chae reports grants from Guardant Health during the conduct of the study; grants from AbbVie, Bristol-Myers Squibb, Biodesix, Lexent Bio, and Freenome; personal fees from Roche/Genentech, AstraZeneca, Foundation Medicine, Counsyl, Neogenomics, Boehringher Ingelheim, Biodesix, Immuneoncia, Lilly Oncology, Merck, and Takeda outside of the submitted work. Dr. Clarke reports other fees from Merck, Achilles Therapeutics, Eli Lilly, AstraZeneca, and Guardant Health during the conduct of the study; grants from Bristol-Myers Squibb, Genentech, Spectrum, Adaptimmune, Medpacto, Bayer, AbbVie, Moderna, Array, and Eli Lilly outside of the submitted work. Dr. Crawford reports grants from AstraZeneca, Genentech, and Helsinn; personal fees from Amgen, AstraZeneca, Coherus, Enzychem, G1 Therapeutics, GlaxoSmithKline, Merck, Pfizer, Spectrum, Beyong Spring, Merrimack, Mylan, and Roche outside of the submitted work. Dr. Meric-Bernstam reports grants and personal fees from eFFECTOR Therapeutics, Pfizer Inc., Seattle Genetics, Puma Biotechnology, DebioPharm, Zymeworks, and Genentech; personal fees from Jackson Laboratory, PACT Pharma, F. Hoffman-La Roche, Paraxel International, IBM Watson, Samsung Bioepis, Aduro Biotech, Kolon Life Sciences, Origimed, Sumitomo Dainippon Pharma, Seattle Genetics, Dialectica, Piers Pharmaceutical, Xencor, Mayo Clinic, Chugai Biopharmaceuticals, Mersana, Immunomedics, Silverback Therapeutics, Inflection Biosciences, Spectrum Pharamceuticals, Grail, Darwin Health, and Clearlight Diagostics; grants from Aileron Therapeutics, AstraZeneca, Bayer HealthCare, Calithera Biosciences, Curis, CytomX Therapeutics, Daiichi Sankyo, Guardant Health, K Group, Millennium Pharmaceuticals, Novartis, PPD Investigator Services, and Taiho Pharmaceutical outside of the submitted work. Dr. Ou reports personal fees from Pfizer, Merck, Takeda/Ariad, Astra Zeneca, Roche/Genentech, Foundation Medicine, Inc., and Spectrum, and other fees from Turning Point Therapeutics outside of the submitted work. Dr. Gandara reports personal fees from Guardant Health during the conduct of the study; grants from Roche- Genentech, Novartis, and Merck; personal fees from AstraZeneca, Celgene, CellMax, FujiFilm, Roche-Genentech, Inivata, IO Biotech, Eli Lilly, Merck, and Samsung Bioepis outside of the submitted work. Dr. Heymach reports personal fees from Genentech during the conduct of the study; personal fees and other fees from Spectrum AstraZeneca and GlaxoSmithKline; personal fees from Boehringer Ingelheim, Exelixis, Genentech, Guardant Health, Hengrui, Eli Lilly, Novartis, and EMD Serono Synta; other fees from Bayer, Takeda, and Biotree outside of the submitted work. Dr. Bivona reports grants from the National Institutes of Health during the conduct of the study; grants and other fees from Novartis and Revolution Medicines; personal fees from AstraZeneca, Takeda, Strategia, Springworks, Array, Pfizer, and Rain outside of the submitted work. Dr. McCoach reports personal fees from Novartis and grants from Revolution Medicines outside of the submitted work. The remaining authors declare no conflict of interest.The authors acknowledge the funding support from the Sheikh Khalifa Al Nahyan Ben Zayed Institute for Personalized Cancer Therapy, Cancer Prevention Research Institutive of Texas Precision Oncology Decision Support Core RP150535 (to Ng and Meric-Bernstam); the National Institutes of Health (NIH)/National Cancer Institute (NCI) U01CA217882, NIH/ NCI U54CA224081, NIH/ NCI R01CA204302, NIH/ NCI R01CA211052, NIH/ NCI R01CA169338, and the Pew-Stewart Foundations (to Bivona); The University of Texas MD Anderson Lung Cancer Moonshots Program, the Lung SPORE grant 5 P50 CA070907, and the MD Anderson Cancer Center Support Grant P30 CA016672 (to Heymach). Dr. Negrao, Raymond, Roarty, Heymach, Bivona, and McCoach contributed to the conception and design of the article. Dr. Negrao, Raymond, Lanman, Ng, Robichaux, He, Nilsson, Amador, Meric-Bernstam, Heymach, Bivona, and McCoach contributed to the development of the methodology of the article. Dr. Negrao, Raymond, Lanman, Ng, Robichaux, He, Nilsson, Amador, Nagy, Banks, Zhu, Ng, Chae, Clarke, Crawford, Meric-Bernstam, Ou, Gandara, Heymach, Bivona, and McCoach contributed to the acquisition of data of the article. Dr. Negrao, Raymond, Robichaux, Nilsson, Amador, Heymach, Bivona, and McCoach contributed to the analysis and interpretation of data of the article. Dr. Negrao, Raymond, Lanman, Ng, Robichaux, He, Nilsson, Amador, Nagy, Banks, Zhu, Roarty, Ng, Chae, Clarke, Crawford, Meric-Bernstam, Ou, Gandara, Heymach, Bivona, and McCoach contributed to the writing, review, and revision of the manuscript of the article. Dr. Negrao, Raymond, Lanman, Ng, Robichaux, He, Nilsson, Amador, Nagy, Banks, Zhu, Roarty, Ng, Chae, Clarke, Crawford, Bivona, Ou, Gandara, Heymach, Bivona, and McCoach contributed to the administrative, technical, or material support of the article. The authors acknowledge the funding support from the Sheikh Khalifa Al Nahyan Ben Zayed Institute for Personalized Cancer Therapy , Cancer Prevention Research Institutive of Texas Precision Oncology Decision Support Core RP150535 (to Ng and Meric-Bernstam); the National Institutes of Health (NIH)/ National Cancer Institute (NCI) U01CA217882 , NIH / NCI U54CA224081 , NIH / NCI R01CA204302 , NIH / NCI R01CA211052 , NIH / NCI R01CA169338 , and the Pew-Stewart Foundations (to Bivona); The University of Texas MD Anderson Lung Cancer Moonshots Program, the Lung SPORE grant 5 P50 CA070907 , and the MD Anderson Cancer Center Support Grant P30 CA016672 (to Heymach). Dr. Negrao, Raymond, Roarty, Heymach, Bivona, and McCoach contributed to the conception and design of the article. Dr. Negrao, Raymond, Lanman, Ng, Robichaux, He, Nilsson, Amador, Meric-Bernstam, Heymach, Bivona, and McCoach contributed to the development of the methodology of the article. Dr. Negrao, Raymond, Lanman, Ng, Robichaux, He, Nilsson, Amador, Nagy, Banks, Zhu, Ng, Chae, Clarke, Crawford, Meric-Bernstam, Ou, Gandara, Heymach, Bivona, and McCoach contributed to the acquisition of data of the article. Dr. Negrao, Raymond, Robichaux, Nilsson, Amador, Heymach, Bivona, and McCoach contributed to the analysis and interpretation of data of the article. Dr. Negrao, Raymond, Lanman, Ng, Robichaux, He, Nilsson, Amador, Nagy, Banks, Zhu, Roarty, Ng, Chae, Clarke, Crawford, Meric-Bernstam, Ou, Gandara, Heymach, Bivona, and McCoach contributed to the writing, review, and revision of the manuscript of the article. Dr. Negrao, Raymond, Lanman, Ng, Robichaux, He, Nilsson, Amador, Nagy, Banks, Zhu, Roarty, Ng, Chae, Clarke, Crawford, Bivona, Ou, Gandara, Heymach, Bivona, and McCoach contributed to the administrative, technical, or material support of the article .
Keywords
- BRAF
- Cell-free DNA
- Non–small cell lung cancer
- Targeted therapy
ASJC Scopus subject areas
- Oncology
- Pulmonary and Respiratory Medicine
