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Nat Med DOI:10.1038/s41591-018-0022-x

Targeting wild-type KRAS-amplified gastroesophageal cancer through combined MEK and SHP2 inhibition.

Publication TypeJournal Article
Year of Publication2018
AuthorsWong, GS, Zhou, J, Bin Liu, J, Wu, Z, Xu, X, Li, T, Xu, D, Schumacher, SE, Puschhof, J, McFarland, J, Zou, C, Dulak, A, Henderson, L, Xu, P, O'Day, E, Rendak, R, Liao, W-L, Cecchi, F, Hembrough, T, Schwartz, S, Szeto, C, Rustgi, AK, Wong, K-K, J Diehl, A, Jensen, K, Graziano, F, Ruzzo, A, Fereshetian, S, Mertins, P, Carr, SA, Beroukhim, R, Nakamura, K, Oki, E, Watanabe, M, Baba, H, Imamura, Y, Catenacci, D, Bass, AJ
JournalNat Med
Date Published2018 May 28
ISSN1546-170X
Abstract

The role of KRAS, when activated through canonical mutations, has been well established in cancer . Here we explore a secondary means of KRAS activation in cancer: focal high-level amplification of the KRAS gene in the absence of coding mutations. These amplifications occur most commonly in esophageal, gastric and ovarian adenocarcinomas. KRAS-amplified gastric cancer models show marked overexpression of the KRAS protein and are insensitive to MAPK blockade owing to their capacity to adaptively respond by rapidly increasing KRAS-GTP levels. Here we demonstrate that inhibition of the guanine-exchange factors SOS1 and SOS2 or the protein tyrosine phosphatase SHP2 can attenuate this adaptive process and that targeting these factors, both genetically and pharmacologically, can enhance the sensitivity of KRAS-amplified models to MEK inhibition in both in vitro and in vivo settings. These data demonstrate the relevance of copy-number amplification as a mechanism of KRAS activation, and uncover the therapeutic potential for targeting of these tumors through combined SHP2 and MEK inhibition.

DOI10.1038/s41591-018-0022-x
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/29808010?dopt=Abstract

Alternate JournalNat. Med.
PubMed ID29808010
Grant ListK23 CA178203 / CA / NCI NIH HHS / United States