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

The role of KRAS, when activated through canonical mutations, has been well established in cancer(1). 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 possess marked overexpression of KRAS protein and are insensitive to MAPK blockade due to their capacity to adaptively respond by rapidly increasing KRAS-GTP levels. We demonstrate that inhibition of guanine exchange factors SOS1/2 or protein tyrosine phosphatase, SHP2, can attenuate this adaptive process and that targeting of these factors, both genetically and pharmacologically, can enhance sensitivity of KRAS-amplified models to MEK inhibition both in 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.