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.

Rapid Improvement of the Performance Status and Reduction of the Tumor Size in KRAS-Mutated Colorectal Cancer Patient Receiving Binimetinib, Hydroxychloroquine, and Bevacizumab

“…The inability to discern the contribution of each single drug is an intrinsic limitation of antitumor combination therapies. In particular, single-agent MEK inhibitors occasionally demonstrated tumor responses in patients with various RAS/RAF-mutated cancers [2,3], so it is not self-explanatory whether the same effect could be achieved with binimetinib alone, or, alternatively, the addition of hydroxychloroquine was critical for the improvement of the health status in this otherwise incurable patient. Bevacizumab was added to binimetinib plus hydroxychloroquine combination purely due to empirical assumptions, given that this drug improves the delivery of various therapies to tumor lumps and based on the extensive experience of using bevacizumab in CRC patients [8].…”

“…Accordingly, pharmacological MEK inhibition demonstrated promising results in preclinical models of RAS/RAF-driven cancers. However, clinical trials involving single-agent MEK inhibitors in patients with RAS and BRAF mutations produced largely disappointing results [2,3]. It was recently shown that the escape of RAS/RAF-mutated tumors from MEK inhibition is mediated by autophagy.…”

“…Recent development of KRAS G12C-specific drugs led to a breakthrough in the treatment of lung cancers carrying this mutation. The design of inhibitors of RAS proteins carrying other amino acid changes turned out to be highly complicated, given that the conformation of mutated RAS enzymes is generally considered “nondruggable.” Consequently, there are attempts to develop “universal” drugs for RAS-driven pathways, which either interfere with the upstream regulation of RAS or counterbalance the consequences of RAS activation [ 1 , 2 , 3 ].…”

Novel regulation of Ras proteins by direct tyrosine phosphorylation and dephosphorylation

“…Mutant GTP-bound Ras acts as a driver that contributes to the pathogenesis of several cancer types. For many decades, Ras was thought to be an "undruggable" cancer target, since no drug against Ras had been approved by authorities [46]. The discovery that SHP2 can dephosphorylate even mutant GTP-bound Ras in tumor cells and release Ras from its inactive state establishes SHP2 as a novel drug target that could be effective in Rasdriven human cancer.…”

Targeting copper metabolism to defeat KRAS-driven colorectal cancer

“…Consequently, almost four decades of intensive research have focused on the development of monotherapeutic approaches to directly or indirectly target oncogenic KRAS. 1 Though early clinical studies have shown some promise, including the recent evaluation of KRAS G12C -specific inhibitors, the emergence of resistance mechanisms has severely limited clinical outcomes. While several different combination therapies are currently being explored to counter drug resistance, the identification of novel vulnerabilities for KRAS-dependent cancers remains important for the design of tailored therapeutic approaches.…”