ReviewCancer therapy

RAS, wanted dead or alive: Advances in targeting RAS mutant cancers

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Science Signaling  24 Mar 2020:
Vol. 13, Issue 624, eaay6013
DOI: 10.1126/scisignal.aay6013

Figures

  • Fig. 1 Defining RAS vulnerabilities for the development of anti-RAS strategies.

    A series of recent studies, addressing different aspects of RAS function, have provided potential clues to targeting RAS for cancer treatment. Where appropriate, clinically approved (red) and investigational (blue) therapeutics indicated for targeting RAS activation and signaling in cancer are noted. Lou et al. (7) applied a CRISPR genetic loss-of-function screen to identify signaling modulators of a small-molecule inhibitor selective for the KRASG12C mutant (I) found predominantly in lung cancer. In contrast to other G12 mutants, KRASG12C retains intrinsic GTP hydrolysis (*with the exception of G12D that retains minor GTP hydrolysis), thereby enabling its targeting by GDP-KRASG12C–specific small molecules. The findings revealed various pathways to target to enhance the potency and durable efficacy of the inhibitor. McFall et al. (22) proposed a mechanism to explain the EGFR dependence of KRASG13D mutant colorectal cancer. Decreased affinity for the RAS-GAP NF1 (II) by the G13D mutant protein enables GAP- and EGFR-dependent regulation of wild-type RAS, thereby retaining sensitivity to EGFR inhibitors in KRASG13D mutant cells. Sheffels et al. (29) identified a role for the RAS-GEF SOS2 (III) in promoting WT HRAS activation of AKT to support MT KRAS-induced transformation of mouse fibroblasts in 3D growth culture conditions.

    CREDIT: A. KITTERMAN/SCIENCE SIGNALING
  • Fig. 2 More RAS vulnerabilities, downstream.

    Insight into additional aspects of RAS protein and pathway regulation reveals more ways to potentially target RAS. Biancucci et al. (17) showed that endopeptidase RRSP modification of RAS (I) impairs its interaction with downstream kinase RAF. Looking further downstream still, Blake et al. (40) applied a MYC degradation screen to identify the kinase CDK9 as a positive regulator of MYC protein stability (II) and, consequently, cell growth and survival. Some clinically approved therapeutics indicated for targeting RAS activation and signaling in cancer are noted (red).

    CREDIT: A. KITTERMAN/SCIENCE SIGNALING

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