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Author: Admin | 2025-04-28
Approved inhibitors are highly selective for the G12C protein isoform and do not inhibit the wild-type RAS receptor coexisting within the same cell. This selective inhibition may provide potential feedback to reactivate the RAS signaling pathways. This reactivation is related to increased NRAS-GTP and HRAS-GTP, suggesting that KRAS G12C–mutant cell lines may rapidly adapt to selective inhibition by activating wild-type RAS and restoring mitogen-activation pathway kinase (MAPK) signaling.40 The increase in wild-type RAS activity results from the activation of several RTKs, including EGFR, human epidermal growth factor receptor 2 (HER2), fibroblast growth factor receptor (FGFR), and cMET.41 Blood-based genomic sequencing of samples collected at the time of adagrasib progression revealed up to 10 distinct mutations affecting effectors of the RAS/MAPK pathway, including activating mutations in NRAS (Q61L/K/R), MAP2K1, and BRAF V600E.36 RTK activation was reported in sotorasib-resistant cells that acquired the epithelial–mesenchymal transition (EMT) phenotype.42 Recent studies have shown that the activation of EMT leads to primary and acquired resistance to KRAS G12C inhibitors. In cells with KRAS G12C inhibitor resistance, EMT is induced via activation of the PI3K pathway, which eventually leads to drug resistance.42 Other KRAS-Targeting Drugs in DevelopmentNew-generation, tri-complex inhibitors of the GTP-bound isoform of the KRAS G12C oncoprotein are currently in development to overcome RTK-mediated tumor escape mechanisms. RMC-6291 is a potent oral tri-complex inhibitor of both KRAS G12C and NRAS G12C that has shown promising antitumor activity in preclinical models of NSCLC.43 RMC-6236 is another potent selective oral RAS tri-complex inhibitor, with antitumor activity in preclinical models of solid tumors with KRAS G12D and G12V mutations, but also in RAS-dependent wild-type tumors as well as RAS-mediated acquired resistance mechanisms.44 Table 2 provides a list of ongoing trials investigating emerging targeted therapies for KRAS-mutated NSCLC.SRC homology phosphatase 2 (SHP2) is a tyrosine phosphatase that promotes activation of the RAS signaling pathway by activating SOS1 and interacting with the SRC kinase, and it also plays a role in KRAS-mutant NSCLC carcinogenesis.45 The preliminary results of the phase 1b CodeBreak 100/101 study, including the combination of sotorasib and the SHP2 inhibitor RMC-4630, were presented at the 2022 World
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