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

By S. Heidorn, C. Milagre, S. Whittaker, Arnaud Nourry, Ion Niculescu-Duvas, N. Dhomen, Jahan Hussain, J. Reis-Filho, C. Springer, C. Pritchard and 1 more. Cell, 2010

1,454 citations recorded by the source corpus.

Summary We 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

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/cdd1e13cc17a992102c0f54bf6002c178deb43fa

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In Molecular Biology

1. C. Der
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4. Walter Kolch
5. Philip E. Bourne
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Citations in the corpus

• Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. (2014, neutral): “Progressive disease 13 (6) 19 (9) 10 (6) 11 (6) 3 (10) 8 (27)”
• RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E) (2011, background): “The sequences are JC-1, 59-GGACAGUGGACUUGAUUAGUU-39; JC-2, 59-AGGA CAGUGGACUUGAUUAUU-39; ex[4-8]-1, 59-ACUGAUAUUUCCUGGCUU AUU-39; ex[4-8]-2, 59-CUGUCAAACAUGUGGUUAUUU-39.”
• RAF inhibitors transactivate RAF dimers and ERK signaling in cells with wild-type BRAF (2010, neutral): “Recently, another model to explain these phenomena has been proposed 23 .”
• Targeting the Mitogen-Activated Protein Kinase RAS-RAF Signaling Pathway in Cancer Therapy (2012, background): “Despite the significant effect of these inhibitors in the treatment of melanoma patients, early studies of these agents in patients with BRAF V600E colorectal carcinoma have thus far been disappointing [86].”