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

Item Type:Article
Title:Targeting wild-type KRAS-amplified gastroesophageal cancer through combined MEK and SHP2 inhibition
Creators Name: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., Schwartz, S., Szeto, C., Rustgi, A.K., Wong, K.K., Diehl, J.A., Jensen, K., Graziano, F., Ruzzo, A., Fereshetian, S., Mertins, P., Carr, S.A., Beroukhim, R., Nakamura, K., Oki, E., Watanabe, M., Baba, H., Imamura, Y., Catenacci, D. and Bass, A.J.
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 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.
Keywords:Tumor Cell Line, Animal Disease Models, Esophageal Neoplasms, Gene Amplification, Mitogen-Activated Protein Kinase Kinases, Piperidines, Protein Kinase Inhibitors, Non-Receptor Type 11 Protein Tyrosine Phosphatase, Proto-Oncogene Proteins p21(ras)/genetics, Pyridones, Pyrimidines, Pyrimidinones, Stomach Neoplasms, Animals, Mice
Source:Nature Medicine
Publisher:Nature Publishing Group
Page Range:968-977
Date:July 2018
Additional Information:Erratum in: Nat Med 24(10), 1625-1628.
Official Publication:https://doi.org/10.1038/s41591-018-0022-x
External Fulltext:View full text on PubMed Central
PubMed:View item in PubMed

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