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Nat Med. 2018 Jul;24(7):968-977. doi: 10.1038/s41591-018-0022-x. Epub 2018 May 28.

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

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
2
Novartis Institutes for Biomedical Research, Inc., Cambridge, MA, USA.
3
Department of Medicine, Section of Hematology/Oncology, University of Chicago Medical Center and Biological Sciences, Chicago, IL, USA.
4
Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
5
Surface Oncology, Cambridge, MA, USA.
6
OncoPlex Diagnostics/NantOmics, Rockville, MD, USA.
7
Division of Gastroenterology, Departments of Medicine and Genetics, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
8
Department of Medicine, Harvard Medical School, Boston, MA, USA.
9
NYU Langone Health, New York, NY, USA.
10
Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA.
11
Sanofi Oncology, Cambridge, MA, USA.
12
University of Illinois at Urbana-Champaign, Chicago, IL, USA.
13
Department of Biomolecular Sciences, University of Urbino "Carlo Bo", Urbino, Italy.
14
Max Delbrück Center for Molecular Medicine, Berlin, Germany.
15
Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
16
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
17
Department of Gastroenterological Surgery, Kumamoto University, Kumamoto, Japan.
18
Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
19
Department of Gastroenterological Surgery, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.
20
Department of Medicine, Section of Hematology/Oncology, University of Chicago Medical Center and Biological Sciences, Chicago, IL, USA. dcatenac@bsd.uchicago.edu.
21
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. adam_bass@dfci.harvard.edu.
22
Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA, USA. adam_bass@dfci.harvard.edu.
23
Department of Medicine, Harvard Medical School, Boston, MA, USA. adam_bass@dfci.harvard.edu.
24
Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. adam_bass@dfci.harvard.edu.

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.

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