Molecular Landscape of BRAF-Mutant NSCLC Reveals an Association Between Clonality and Driver Mutations and Identifies Targetable Non-V600 Driver Mutations.
BRAF
Cell-free DNA
Non–small cell lung cancer
Targeted therapy
Journal
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
ISSN: 1556-1380
Titre abrégé: J Thorac Oncol
Pays: United States
ID NLM: 101274235
Informations de publication
Date de publication:
10 2020
10 2020
Historique:
received:
06
02
2020
revised:
22
03
2020
accepted:
05
05
2020
pubmed:
17
6
2020
medline:
2
2
2021
entrez:
17
6
2020
Statut:
ppublish
Résumé
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-mutant NSCLC cell lines than other MEK, BRAF, and ERK inhibitors, comparable with the inhibition of BRAF V600E cell line. 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.
Identifiants
pubmed: 32540409
pii: S1556-0864(20)30466-4
doi: 10.1016/j.jtho.2020.05.021
pmc: PMC7529990
mid: NIHMS1614717
pii:
doi:
Substances chimiques
Protein Kinase Inhibitors
0
BRAF protein, human
EC 2.7.11.1
Proto-Oncogene Proteins B-raf
EC 2.7.11.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1611-1623Subventions
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA217882
Pays : United States
Organisme : NCI NIH HHS
ID : U54 CA224081
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA211052
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA070907
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA169338
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA204302
Pays : United States
Informations de copyright
Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
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