Mapping the molecular determinants of BRAF oncogene dependence in human lung cancer

Luping Lin, Saurabh Asthana, Elton Chan, Sourav Bandyopadhyay, Maria M. Martins, Victor Olivas, Jenny Jiacheng Yan, Luu Pham, Mingxue Michelle Wang, Gideon Bollag, David B. Solit, Eric A. Collisson, Charles M. Rudin, Barry S. Taylor, Trever G. Bivona

Research output: Contribution to journalArticle

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 BRAFV600E, but not other BRAF mutations, initially are sensitive to BRAF-inhibitor treatment. However, these BRAFV600E NSCLC cells rapidly acquire resistance to BRAF inhibition through at least one of two discrete molecular mechanisms: (i) loss of full-length BRAFV600E coupled with expression of an aberrant form of BRAFV600E that retains RAF pathway dependence or (ii) constitutive autocrine EGF receptor (EGFR) signaling driven by c-Jun-mediated EGFR ligand expression. BRAFV600E 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.

Original languageEnglish (US)
Pages (from-to)E748-E757
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number7
DOIs
StatePublished - Feb 18 2014
Externally publishedYes

Keywords

  • Combination therapy
  • Targeted therapy

ASJC Scopus subject areas

  • General

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  • Cite this

    Lin, L., Asthana, S., Chan, E., Bandyopadhyay, S., Martins, M. M., Olivas, V., Yan, J. J., Pham, L., Wang, M. M., Bollag, G., Solit, D. B., Collisson, E. A., Rudin, C. M., Taylor, B. S., & Bivona, T. G. (2014). Mapping the molecular determinants of BRAF oncogene dependence in human lung cancer. Proceedings of the National Academy of Sciences of the United States of America, 111(7), E748-E757. https://doi.org/10.1073/pnas.1320956111