title: Mapping the molecular determinants of BRAF oncogene dependence in human lung cancer.
abstract: Oncogenic mutations in the BRAF kinase occur in 6-8% of nonsmall cell lung cancers (NSCLCs), accounting for more than 90,000 deaths annually worldwide. The biological and clinical relevance of these BRAF mutations in NSCLC is incompletely understood. Here we demonstrate that human NSCLC cells with BRAF(V600E), but not other BRAF mutations, initially are sensitive to BRAF-inhibitor treatment. However, these BRAF(V600E) NSCLC cells rapidly acquire resistance to BRAF inhibition through at least one of two discrete molecular mechanisms: (i) loss of full-length BRAF(V600E) coupled with expression of an aberrant form of BRAF(V600E) that retains RAF pathway dependence or (ii) constitutive autocrine EGF receptor (EGFR) signaling driven by c-Jun-mediated EGFR ligand expression. BRAF(V600E) cells with EGFR-driven resistance are characterized by hyperphosphorylated protein kinase AKT, a biomarker we validated in BRAF inhibitor-resistant NSCLC clinical specimens. These data reveal the multifaceted molecular mechanisms by which NSCLCs establish and regulate BRAF oncogene dependence, provide insights into BRAF-EGFR signaling crosstalk, and uncover mechanism-based strategies to optimize clinical responses to BRAF oncogene inhibition.
authors.affiliation: Departments of Medicine and Epidemiology and Biostatistics and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94158.
authors.forename: Luping
authors.initials: L
authors.lastname: Lin
authors.forename: Saurabh
authors.initials: S
authors.lastname: Asthana
authors.forename: Elton
authors.initials: E
authors.lastname: Chan
authors.forename: Sourav
authors.initials: S
authors.lastname: Bandyopadhyay
authors.forename: Maria M
authors.initials: MM
authors.lastname: Martins
authors.forename: Victor
authors.initials: V
authors.lastname: Olivas
authors.forename: Jenny Jiacheng
authors.initials: JJ
authors.lastname: Yan
authors.forename: Luu
authors.initials: L
authors.lastname: Pham
authors.forename: Mingxue Michelle
authors.initials: MM
authors.lastname: Wang
authors.forename: Gideon
authors.initials: G
authors.lastname: Bollag
authors.forename: David B
authors.initials: DB
authors.lastname: Solit
authors.forename: Eric A
authors.initials: EA
authors.lastname: Collisson
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rudin
authors.forename: Barry S
authors.initials: BS
authors.lastname: Taylor
authors.forename: Trever G
authors.initials: TG
authors.lastname: Bivona
mesh_terms: D019898:Autocrine Communication / Q000235:genetics / Q000502:physiology*; D001483:Base Sequence; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010766:Phosphorylation; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics*; D017423:Sequence Analysis, RNA
chemical_list: D066246:ErbB Receptors; C482119:BRAF protein, human; D051058:Oncogene Protein v-akt; D048493:Proto-Oncogene Proteins B-raf
keywords: combination therapy; targeted therapy