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

ABSTRACT: The role of KRAS, when activated through canonical mutations, has been well established in cancer¹. 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^2-4. 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 pharmacologica

SUBMITTER: Wong GS 

PROVIDER: S-EPMC6039276 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature