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 adenocarcinomas2,3,4. 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.
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This research was supported by funding from Target Cancer Foundation, Sanofi Oncology (A.J.B., G.S.W. and K.J.), Twomey Family Fellowship in Esophageal Cancer Research (G.S.W. and J.Z.), a Research Scholar Grant from the American Cancer Society to A.J.B. and NIH grants P50 CA127003 (A.J.B.). A.J.B., K.-K.W., J.A.D. and A.K.R. were supported by NIH grant P01 CA098101. JSPS Kakenhi grant JP16H06259 and Kobayashi Foundation for Cancer Research supported Y.I. D.C. was supported by the Live Like Katie (LLK) Fund, Sal Ferrara II Fund for PANGEA, NIH K23 CA178203-01A1, University of Chicago Comprehensive Cancer Center (UCCCC) Precision Oncology-Cancer Center Support Grant P30 CA014599.
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Nature Communications (2019)
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