The Role of Wild-Type RAS in Oncogenic RAS Transformation

Overview

Journal Genes (Basel)

Publisher MDPI

Date 2021 Apr 30

PMID 33924994

Citations 21

Authors

Erin Sheffels

Robert L Kortum

Affiliations

Soon will be listed here.

Abstract

The family of oncogenes (, , and ) are among the most frequently mutated protein families in cancers. -mutated tumors were originally thought to proliferate independently of upstream signaling inputs, but we now know that non-mutated wild-type (WT) RAS proteins play an important role in modulating downstream effector signaling and driving therapeutic resistance in -mutated cancers. This modulation is complex as different WT RAS family members have opposing functions. The protein product of the allele of the same isoform as mutated is often tumor-suppressive and lost during tumor progression. In contrast, RTK-dependent activation of the WT RAS proteins from the two non-mutated WT family members is tumor-promoting. Further, rebound activation of RTK-WT RAS signaling underlies therapeutic resistance to targeted therapeutics in -mutated cancers. The contributions of WT RAS to proliferation and transformation in -mutated cancer cells places renewed interest in upstream signaling molecules, including the phosphatase/adaptor SHP2 and the RasGEFs SOS1 and SOS2, as potential therapeutic targets in -mutated cancers.

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