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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 adenocarcinomas2,3,4. 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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Change history

  • 09 August 2018

    In the Supplementary Information originally published with this article, a lane was missing in the β-actin blot in Supplementary Fig. 2. The lane has been added. The error has been corrected in the Supplementary Information associated with this article.

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Acknowledgements

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.

Author information

Author notes

    • Gabrielle S. Wong

    Present address: Novartis Institutes for Biomedical Research, Inc., Cambridge, MA, USA

    • Austin Dulak

    Present address: Surface Oncology, Cambridge, MA, USA

    • Karin Jensen

    Present address: University of Illinois at Urbana-Champaign, Chicago, IL, USA

    • Philipp Mertins

    Present address: Max Delbrück Center for Molecular Medicine, Berlin, Germany

  1. These authors contributed equally: Jin Zhou and Jie Bin Liu.

Affiliations

  1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    • Gabrielle S. Wong
    • , Jin Zhou
    • , Jie Bin Liu
    • , Zhong Wu
    • , Xinsen Xu
    • , Tianxia Li
    • , Jens Puschhof
    • , James McFarland
    • , Charles Zou
    • , Austin Dulak
    • , Rameen Beroukhim
    •  & Adam J. Bass
  2. Department of Medicine, Section of Hematology/Oncology, University of Chicago Medical Center and Biological Sciences, Chicago, IL, USA

    • David Xu
    • , Les Henderson
    • , Peng Xu
    • , Emily O’Day
    • , Rachel Rendak
    •  & Daniel Catenacci
  3. Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA, USA

    • Steven E. Schumacher
    • , James McFarland
    • , Shaunt Fereshetian
    • , Philipp Mertins
    • , Steven A. Carr
    • , Rameen Beroukhim
    •  & Adam J. Bass
  4. OncoPlex Diagnostics/NantOmics, Rockville, MD, USA

    • Wei-li Liao
    • , Fabiola Cecchi
    • , Todd Hembrough
    • , Sarit Schwartz
    •  & Christopher Szeto
  5. Division of Gastroenterology, Departments of Medicine and Genetics, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    • Anil K. Rustgi
  6. Department of Medicine, Harvard Medical School, Boston, MA, USA

    • Kwok-Kin Wong
    • , Rameen Beroukhim
    •  & Adam J. Bass
  7. NYU Langone Health, New York, NY, USA

    • Kwok-Kin Wong
  8. Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA

    • J. Alan Diehl
  9. Sanofi Oncology, Cambridge, MA, USA

    • Karin Jensen
  10. Department of Biomolecular Sciences, University of Urbino “Carlo Bo”, Urbino, Italy

    • Francesco Graziano
    •  & Annamaria Ruzzo
  11. Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA

    • Rameen Beroukhim
    •  & Adam J. Bass
  12. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA

    • Rameen Beroukhim
  13. Department of Gastroenterological Surgery, Kumamoto University, Kumamoto, Japan

    • Kenichi Nakamura
    • , Masayuki Watanabe
    • , Hideo Baba
    •  & Yu Imamura
  14. Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    • Eiji Oki
  15. Department of Gastroenterological Surgery, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan

    • Masayuki Watanabe
    •  & Yu Imamura

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Contributions

G.S.W., A.J.B. and D.C. conceived the study and wrote and edited the manuscript. G.S.W., J.Z., J.B.L., Z.W., T.L., X.X., J.P., C.Z., A.D. and K.J. participated in the planning, data generation and analysis of in vitro and biochemical experiments. G.S.W., J.Z., J.B.L. and Z.W. performed tumor xenograft experiments. S.E.S., J.M., S.F., P.M., S.A.C. and R.B. performed genomic analysis. D.X., L.H., P.X., E.O’D., R.R., W.-l.L., F.C., T.H., S.S. and C.S. developed and maintained patient-derived cell lines, performed histochemical and mass spectrometric analysis. F.G., A.R., K.N., E.O., M.W., H.B. and Y.I. performed immunohistochemical and retrospective clinical outcomes analysis. A.K.R., K.-K.W. and J.A.D. provided critical input. All authors read and edited the manuscript.

Competing interests

G.S.W. is now an employee of Novartis Institutes for Biomedical Research, Inc.

Corresponding authors

Correspondence to Daniel Catenacci or Adam J. Bass.

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https://doi.org/10.1038/s41591-018-0022-x

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