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

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.

journal_name

Nat Med

journal_title

Nature medicine

authors

Wong GS,Zhou J,Liu JB,Wu Z,Xu X,Li T,Xu D,Schumacher SE,Puschhof J,McFarland J,Zou C,Dulak A,Henderson L,Xu P,O'Day E,Rendak R,Liao WL,Cecchi F,Hembrough T,Schwartz S,Szeto C,Rustgi AK,Wong KK,Diehl JA,Jen

doi

10.1038/s41591-018-0022-x

subject

Has Abstract

pub_date

2018-07-01 00:00:00

pages

968-977

issue

7

eissn

1078-8956

issn

1546-170X

pii

10.1038/s41591-018-0022-x

journal_volume

24

pub_type

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