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

Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer
Marcelo V NegraoCaroline E McCoach

Abstract

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. 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. 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-mu...Continue Reading

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Nov 21, 2020·Oncotarget·Douglas B JohnsonMarcus S Noel
Mar 12, 2021·Current Oncology·Alla Turshudzhyan, James Vredenburgh
Dec 15, 2020·Trends in Cancer·Marie-Julie NokinDavid Santamaria
Sep 29, 2020·Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer·Ibiayi Dagogo-Jack

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