Heidorn SJ, Milagre C, Whittaker S et al.Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell 140:209-221

The Institute of Cancer Research, Signal Transduction Team, Section of Cell and Molecular Biology, 237 Fulham Road, London SW3 6JB, UK.
Cell (Impact Factor: 32.24). 01/2010; 140(2):209-21. DOI: 10.1016/j.cell.2009.12.040
Source: PubMed


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.


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    • "Crystal structures of BRAF in complex with vemurafenib and its analog PLX4720 revealed an asymmetric dimer in which only one of the two ATP sites was effectively occupied by the drug (Bollag et al., 2010, 2012; Tsai et al., 2008). By binding to one RAF subunit and promoting dimer formation, the BRAF selective inhibitors activate the second drug-free partner, by either altering subcellular localization or propagating a conformational change to the drug-free protomer (Heidorn et al., 2010; Poulikakos et al., 2010). Based on the outlined model, we hypothesized that in order to block paradoxical activation, a RAF inhibitor must effectively inhibit not only all RAF isoforms, but also the active RAF homo-and hetero-dimers. "
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    • "In contrast, BGB659, a type II, ATPcompetitive RAF inhibitor (compound 27 from Gould et al., 2011), inhibited ERK signaling driven by p61 BRAF V600E dimers and BRAF V600E monomers at similar doses (Figures 4B and S4D). Its inhibition of ERK signaling is mediated by its binding to BRAF; the T529 BRAF gatekeeper mutation (Heidorn et al., 2010) confers resistance to the drug (Figure S4E). In cells that express either BRAF V600E T529N or p61 BRAF V600E T529N, ERK signaling is resistant to both vemurafenib and BGB659 but not to the MEK inhibitor trametinib. "
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    • "Interestingly , vemurafenib can paradoxically activate the MAPK pathway via heterodimerization of BRAF and CRAF kinases to promote growth in tumors harboring wild-type BRAF or activating RAS mutations. Therefore, vemurafenib monotherapy should not be used in patients with advanced melanoma with wildtype BRAF or RAS mutation (Heidorn et al., 2010; Poulikakos, Zhang, Bollag, & Shokat, 2010; Hatzivassiliou et al., 2010). "
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