| Literature DB >> 30300582 |
Ivana Yen1, Frances Shanahan1, Mark Merchant2, Christine Orr2, Thomas Hunsaker2, Matthew Durk3, Hank La3, Xiaolin Zhang3, Scott E Martin1, Eva Lin1, John Chan1, Yihong Yu1, Dhara Amin1, Richard M Neve1, Amy Gustafson4, Avinashnarayan Venkatanarayan1, Scott A Foster1, Joachim Rudolph5, Christiaan Klijn6, Shiva Malek7.
Abstract
Targeting KRAS mutant tumors through inhibition of individual downstream pathways has had limited clinical success. Here we report that RAF inhibitors exhibit little efficacy in KRAS mutant tumors. In combination drug screens, MEK and PI3K inhibitors synergized with pan-RAF inhibitors through an RAS-GTP-dependent mechanism. Broad cell line profiling with RAF/MEK inhibitor combinations revealed synergistic efficacy in KRAS mutant and wild-type tumors, with KRASG13D mutants exhibiting greater synergy versus KRASG12 mutant tumors. Mechanistic studies demonstrate that MEK inhibition induced RAS-GTP levels, RAF dimerization and RAF kinase activity resulting in MEK phosphorylation in synergistic tumor lines regardless of KRAS status. Taken together, our studies uncover a strategy to rewire KRAS mutant tumors to confer sensitivity to RAF kinase inhibition.Entities:
Keywords: BRAF; CRAF; KRAS; MAPK; MEK inhibitors; PI3K inhibitors; RAF inhibitors; RAS-GTP; cancer; combination treatment
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Year: 2018 PMID： 30300582 DOI： 10.1016/j.ccell.2018.09.002
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743