Molecular Landscape of BRAF-Mutant NSCLC Reveals an Association Between Clonality and Driver Mutations and Identifies Targetable Non-V600 Driver Mutations.

Autor:	Negrao MV; Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Raymond VM; Guardant Health, Redwood City, California., Lanman RB; Guardant Health, Redwood City, California., Robichaux JP; Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., He J; Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Nilsson MB; Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Ng PKS; Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas., Amador BE; Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas., Roarty EB; Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Nagy RJ; Guardant Health, Redwood City, California., Banks KC; Guardant Health, Redwood City, California., Zhu VW; Chao Family Comprehensive Cancer Center, Department of Medicine, Division of Hematology-Oncology, University of California Irvine, Orange, California., Ng C; Kaiser Permanente, Stockton, California., Chae YK; Robert H. Lurie Comprehensive Cancer Center, Division of Hematology-Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois., Clarke JM; Duke Cancer Center, Raleigh, Durham, North Calorina., Crawford JA; Duke Cancer Institute, Raleigh, Durham, North Calorina., Meric-Bernstam F; Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas., Ignatius Ou SH; Chao Family Comprehensive Cancer Center, Department of Medicine, Division of Hematology-Oncology, University of California Irvine, Orange, California., Gandara DR; Division of Hematology-Oncology, Department of Internal Medicine, University of California Davis Comprehensive Cancer Center, Sacramento, California., Heymach JV; Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Bivona TG; Division of Hematology and Oncology, University of California San Francisco, San Francisco, California., McCoach CE; Division of Hematology and Oncology, University of California San Francisco, San Francisco, California. Electronic address: caroline.mccoach@ucsf.edu.
Jazyk:	angličtina
Zdroj:	Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer [J Thorac Oncol] 2020 Oct; Vol. 15 (10), pp. 1611-1623. Date of Electronic Publication: 2020 Jun 13.
DOI:	10.1016/j.jtho.2020.05.021
Abstrakt:	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. (Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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