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

Gabrielle S. Wong, Jin Zhou, Jie Bin Liu, Zhong Wu, Xinsen Xu, Tianxia Li, David Xu, Steven E. Schumacher, Jens Puschhof, James McFarland, Charles Zou, Austin Dulak, Les Henderson, Peng Xu, Emily O'Day, Rachel Rendak, Wei Li Liao, Fabiola Cecchi, Todd Hembrough, Sarit SchwartzChristopher Szeto, Anil K. Rustgi, Kwok Kin Wong, J. Alan Diehl, Karin Jensen, Francesco Graziano, Annamaria Ruzzo, Shaunt Fereshetian, Philipp Mertins, Steven A. Carr, Rameen Beroukhim, Kenichi Nakamura, Eiji Oki, Masayuki Watanabe, Hideo Baba, Yu Imamura, Daniel Catenacci, Adam J. Bass

Research output: Contribution to journalArticle

Abstract

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 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.

Original languageEnglish (US)
Pages (from-to)968-977
Number of pages10
JournalNature Medicine
Volume24
Issue number7
DOIs
StatePublished - Jul 1 2018

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Wong, G. S., Zhou, J., Liu, J. B., Wu, Z., Xu, X., Li, T., Xu, D., Schumacher, S. E., Puschhof, J., McFarland, J., Zou, C., Dulak, A., Henderson, L., Xu, P., O'Day, E., Rendak, R., Liao, W. L., Cecchi, F., Hembrough, T., ... Bass, A. J. (2018). Targeting wild-type KRAS-amplified gastroesophageal cancer through combined MEK and SHP2 inhibition letter. Nature Medicine, 24(7), 968-977. https://doi.org/10.1038/s41591-018-0022-x