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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 adenocarcinomas2-4. 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 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.

SUBMITTER: Wong GS 

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

REPOSITORIES: biostudies-literature

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

Wong Gabrielle S GS   Zhou Jin J   Liu Jie Bin JB   Wu Zhong Z   Xu Xinsen X   Li Tianxia T   Xu David D   Schumacher Steven E SE   Puschhof Jens J   McFarland James J   Zou Charles C   Dulak Austin A   Henderson Les L   Xu Peng P   O'Day Emily E   Rendak Rachel R   Liao Wei-Li WL   Cecchi Fabiola F   Hembrough Todd T   Schwartz Sarit S   Szeto Christopher C   Rustgi Anil K AK   Wong Kwok-Kin KK   Diehl J Alan JA   Jensen Karin K   Graziano Francesco F   Ruzzo Annamaria A   Fereshetian Shaunt S   Mertins Philipp P   Carr Steven A SA   Beroukhim Rameen R   Nakamura Kenichi K   Oki Eiji E   Watanabe Masayuki M   Baba Hideo H   Imamura Yu Y   Catenacci Daniel D   Bass Adam J AJ  

Nature medicine 20180528 7


The role of KRAS, when activated through canonical mutations, has been well established in cancer<sup>1</sup>. 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<sup>2-4</sup>. KRAS-amplified gastric cancer models show marked overexpression of the KRAS protein and are insensitive to MAPK blockade owing to thei  ...[more]

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