Kinase-Dead BRAF and Oncogenic RAS Cooperate to Drive Tumor Progression through CRAF

Abstract

SummaryWe describe a mechanism of tumorigenesis mediated by kinase-dead BRAF in the presence of oncogenic RAS. We show that drugs that selectively inhibit BRAF drive RAS-dependent BRAF binding to CRAF, CRAF activation, and MEK–ERK signaling. This does not occur when oncogenic BRAF is inhibited, demonstrating that BRAF inhibition per se does not drive pathway activation; it only occurs when BRAF is inhibited in the presence of oncogenic RAS. Kinase-dead BRAF mimics the effects of the BRAF-selective drugs and kinase-dead Braf and oncogenic Ras cooperate to induce melanoma in mice. Our data reveal another paradigm of BRAF-mediated signaling that promotes tumor progression. They highlight the importance of understanding pathway signaling in clinical practice and of genotyping tumors prior to administering BRAF-selective drugs, to identify patients who are likely to respond and also to identify patients who may experience adverse effects.PaperClip

Synergistic cytotoxicity of radiation and oncolytic Lister strain vaccinia in V600D/EBRAF mutant melanoma depends on JNK and TNF-α signaling

“…For example, the finding that approximately 50% of melanomas harbour oncogenic BRAF mutations has driven drug discovery programmes that have generated potent, selective inhibitors that are active against V600E BRAF mutant tumor cells (25)(26)(27). These agents have yielded dramatic results in clinical trials in patients with V600E BRAF mutant melanoma (28,29).…”

“…These observations highlight the need for continued research effort in to novel therapies for BRAF mutant melanoma. As a note of caution, however, the importance of a detailed understanding of the molecular pathology of MMM was underlined in preclinical work that showed that, in BRAF wild-type tumor cells, the use of a BRAF inhibitor can activate signalling through BRAF-CRAF dimerisation and, as a result, may accelerate tumor growth (27). Therefore, future development of specific targeted therapies for MMM must include a detailed analysis of the various genetic backgrounds of this disease.…”

Targeted agents and immunotherapies: optimizing outcomes in melanoma

“…This work was essential in identifying MEK as being of particular importance in BRAF-inhibitor resistance and, thus, the potential synergy between BRAF and MEK inhibitors 55 . The mechanistic specificity of this work additionally led to the description of a phenomenon dubbed 'paradoxical activation' of the MAPK pathway via BRAF inhibition in BRAF-wild-type cells, for example, keratinocytes [56][57][58][59] . This discovery suggested that some of the hyperproliferative cutaneous manifestations associated with BRAF inhibition in the clinic might be mitigated by combination therapy incorporating a MEK inhibitor.…”

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