Journal
NATURE MEDICINE
Volume 24, Issue 7, Pages 968-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41591-018-0022-x
Keywords
-
Funding
- Target Cancer Foundation, Sanofi Oncology
- Twomey Family Fellowship in Esophageal Cancer Research
- American Cancer Society
- NIH [P01 CA098101, K23 CA178203-01A1]
- JSPS Kakenhi [JP16H06259]
- Kobayashi Foundation for Cancer Research
- Live Like Katie (LLK) Fund
- Sal Ferrara II Fund for PANGEA
- University of Chicago Comprehensive Cancer Center (UCCCC) Precision Oncology-Cancer Center [P30 CA014599]
- NATIONAL CANCER INSTITUTE [P01CA098101, P50CA127003, P30CA014599, K23CA178203] Funding Source: NIH RePORTER
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available