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

Wong, Gabrielle and Zhou, Jin and Liu, Jie Bin and Xu, Xinsen and Wu, Zhong and Xu, David and Schumacher, Steven and Puschhof, Jens and Li, Tianxia and McFarland, James and Zou, Charles and Dulak, Austin and Henderson, Les and Xu, Peng and O'Day, Emily and Rendak, Rachel and Liao, Wei-li and Cecchi, Fabiola and Hembrough, Todd and Schwartz, Sarit and Szeto, Christopher and Rustgi, Anil and Wong, Kwok-kin and Diehl, J.Alan and Jensen, Karin and Graziano, Federico and Ruzzo, Annamaria and Fereshetian, Shaunt and Mertins, Philipp and Carr, Steven and Beroukhim, Rameen and Nakamura, Kenichi and Oki, Eiji and Watanabe, Masayuki and Baba, Hideo and Imamura, Yu and Catenacci, Daniel and Bass, Adam (2018) Targeting wild-type KRAS-amplified gastroesophageal cancer through combined MEK and SHP2 inhibition. Nature medicine. ISSN 1078-8956

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 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 amplification to be an under-recognized means of KRAS activation, that tumors with these amplifications have unique adaptive physiology and that SOS or SHP2 blockade has potential to be a critical component of new therapies for these cancers.

Item Type: Article
Date Deposited: 24 Jul 2018 00:45
Last Modified: 24 Jul 2018 00:45
URI: https://oak.novartis.com/id/eprint/34904

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