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.targeted therapy | combination therapy

The Hippo effector YAP regulates the response of cancer cells to MAPK pathway inhibitors

“…4,5 Resistance to RAF-MEK targeted therapy is a major clinical challenge. RAF-MEK inhibitors are initially, but only transiently, effective in some, but not all, patients with BRAF-mutant disease, and largely ineffective in patients with RASmutant disease because of resistance.…”

Preclinical efficacy of a RAF inhibitor that evades paradoxical MAPK pathway activation in protein kinase BRAF -mutant lung cancer

“…We found that treatment with erlotinib (at a concentration we showed suppresses p-EGFR levels in HCC364 cells; ref. 4) or everolimus alone suppressed cell growth and MAPK, PI-3 kinase, and mTORC1-S6 signaling in the PLX8394-resistant cells, with little impact on cell growth in the parental cells (Fig. 3 C-E).…”

“…We recently showed that BRAF V600E LA cells (HCC364) can acquire vemurafenib resistance by expressing an aberrant (truncated) splice variant of BRAF V600E that is vemurafenib-insensitive and constitutively dimerized (4). We tested whether the enhanced efficacy of PLX8394 versus vemurafenib extended to these vemurafenib-insensitive cells (HCC364VR1).…”

“…Mutant BRAF promotes tumor growth by hyperactivating the RAF-MEK-ERK signaling cascade (2)(3)(4)(5). BRAF V600E is the most common oncogenic form of BRAF in most tumor types, and selective RAF inhibitors such as vemurafenib and dabrafenib have demonstrated clinical efficacy in melanoma and LA harboring BRAF V600E (6)(7)(8)(9).…”

“…BRAF V600E is the most common oncogenic form of BRAF in most tumor types, and selective RAF inhibitors such as vemurafenib and dabrafenib have demonstrated clinical efficacy in melanoma and LA harboring BRAF V600E (6)(7)(8)(9). Despite these findings, ∼15% of BRAF mutant cancers do not respond to BRAF inhibitors, and the majority of patients who achieve a response will inevitably acquire resistance to these targeted agents, predominantly through reactivation of MAPK pathway signaling (4,(10)(11)(12)(13)(14)(15)(16).…”