Abstract
RAS oncogenes are chief tumorigenic drivers, and their mutation constitutes a universal predictor of poor outcome and treatment resistance. Despite more than 30 years of intensive research since the identification of the first RAS mutation, most attempts to therapeutically target RAS mutants have failed to reach the clinic. In fact, the first mutant RAS inhibitor, Sotorasib, was only approved by the FDA until 2021. However, since Sotorasib targets the KRAS G12C mutant with high specificity, relatively few patients will benefit from this therapy. On the other hand, indirect approaches to inhibit the RAS pathway have revealed very intricate cascades involving feedback loops impossible to overcome with currently available therapies. Some of these mechanisms play different roles along the multistep carcinogenic process. For instance, although mutant RAS increases replicative, metabolic and oxidative stress, adaptive responses alleviate these conditions to preserve cellular survival and avoid the onset of oncogene-induced senescence during tumorigenesis. The resulting rewiring of cellular mechanisms involves the DNA damage response and pathways associated with oxidative stress, which are co-opted by cancer cells to promote survival, proliferation, and chemo- and radioresistance. Nonetheless, these systems become so crucial to cancer cells that they can be exploited as specific tumor vulnerabilities. Here, we discuss key aspects of RAS biology and detail some of the mechanisms that mediate chemo- and radiotherapy resistance of mutant RAS cancers through the DNA repair pathways. We also discuss recent progress in therapeutic RAS targeting and propose future directions for the field.
Highlights
Reviewed by: Sezen Vatansever, Icahn School of Medicine at Mount Sinai, United States Samantha Messina, Roma Tre University, Italy
G12C targeting with the recently approved covalent inhibitor Sotorasib is very specific for the mutant protein, but this brilliant approach’s high selectivity comes at the price of benefiting a relatively small percentage of patients, as previously mentioned (Hansen et al, 2018; Kim et al, 2021)
Advances have been achieved in tackling RAS vulnerabilities by exploiting a recently discovered co-dependence between mutant Kirsten rat sarcoma viral oncogene (KRAS) and the component of the alternative NHEJ pathway PARP1
Summary
The Ras superfamily is composed of structurally and mechanistically related small GTPase proteins organized in five major families named Ras, Rho, Arf, Ran, and Rab. Mutations in KRAS are the most common, accounting for ~85% of all RAS mutations, followed by 12% for NRAS, and 3% for HRAS (Simanshu et al, 2017) These alterations lead to critical amino acid substitutions which generate a constitutively active RAS protein, due to the impairment of GAP binding or decreased GTP hydrolysis (Smith et al, 2013). KRAS G12C inhibitors thwart the GTPase’s preference to favour GDP binding over GTP, concomitantly inhibiting its signalling activity by precluding RAS interaction with RAF (Ostrem et al, 2013) Since these compounds target a mutant cysteine, they spare the WT protein, underscoring their suitability as cancer therapeutic agents (McCormick, 2020).
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