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

Abstract

Oncogenic RAS proteins, which are mutated in approximately 24% of all human cancers, have earned a well-deserved reputation as being "undruggable." However, several studies have challenged that reputation. With the first small molecules that directly target one oncogenic RAS mutant (G12C) undergoing clinical evaluation, there have been substantial advances in finding anti-RAS therapeutic strategies. Furthermore, new insights have come from the growing appreciation that neither all RAS proteins (HRAS, NRAS, and KRAS4A/KRAS4B) nor all oncogenic RAS mutations (such as at residues Gly¹², Gly¹³, and Gln⁶¹) have the same impact on RAS signaling and function. The role of the nonmutated, wild-type RAS proteins in the context of mutant RAS is increasingly considered to be targetable, with reports of strategies that directly disrupt either the RAS interaction with activating guanine nucleotide exchange factors (GEFs) or receptor tyrosine kinase-mediated and GEF-dependent RAS activation (such as by targeting the scaffolding phosphatase SHP2). Last, the development of agents that target downstream effectors of RAS signaling has advanced substantially. In this review, we highlight some important trends in the targeting of RAS proteins in cancer.

Figure 1.. Defining novel RAS vulnerabilities for the development of anti-RAS strategies.

A series of recent studies, addressing different aspects of RAS function, have provided potential new 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. applied a CRISPR genetic loss-of-function screen to identify signaling modulators of a small molecule inhibitor selective for the KRAS^G12C mutant (I) found predominantly in lung cancer. In contrast to other G12 mutants, KRAS^G12C retains intrinsic GTP-hydrolysis (*with the exception of G12D which retains minor GTP-hydrolysis), thereby enabling its’ targeting by GDP-KRAS^G12C-specific small molecules. The findings revealed various pathways to target to enhance the potency and durable efficacy of the inhibitor. McFall et al. proposed a mechanism to explain the EGFR-dependence of KRAS^G13D-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 KRAS^G13D-mutant cells. And Sheffels et al. identified a role for the RAS-GEF SOS2 (III) in promoting WT HRAS activation of AKT to support mutant KRAS-induced transformation of mouse fibroblasts in 3D growth culture conditions.

Figure 2.. More RAS vulnerabilities, downstream.

Insight into additional aspects of RAS protein and pathway regulation reveal more ways to potentially target RAS. Biancucci et al. showed that endopeptidase RRSP modification of RAS (I) impairs its interaction with downstream kinase RAF. Looking further downstream still, Blake et al. 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).