When cancer cells are exposed to growth factors like EGF or HGF, both old and new KRAS G12C drugs lose effectiveness equally, because other related proteins (HRAS and NRAS) become activated and bypass the blocked KRAS pathway.
Evidence from Studies
No evidence studies found yet.
What Would Prove This
Per GRADE and EBM methodology, here is what ideal scientific evidence would look like to definitively prove or disprove this claim, ordered from strongest to weakest.
Whether combining KRAS G12C inhibitors with RTK or pan-RAS inhibitors improves clinical outcomes in patients whose tumors show evidence of HRAS/NRAS activation at baseline or upon progression.
A systematic review and meta-analysis of all phase II/III trials evaluating KRAS G12C inhibitors combined with SOS1 inhibitors, MEK inhibitors, or pan-RAS inhibitors in patients with KRAS G12C-mutant cancers, stratified by baseline HRAS/NRAS activation status (via pERK or RAS-GTP assays), with primary endpoint of progression-free survival.
Whether adding a pan-RAS inhibitor to a KRAS G12C inhibitor overcomes growth factor-mediated resistance in patients with KRAS G12C-mutant cancers.
A double-blind, randomized controlled trial of 200+ patients with KRAS G12C-mutant NSCLC who have progressed on a KRAS G12C inhibitor, randomized to receive either a pan-RAS inhibitor (e.g., RMC-6236) plus the same KRAS G12C inhibitor or placebo plus the same KRAS G12C inhibitor, with primary endpoint of progression-free survival and secondary endpoint of RAS-GTP levels in ctDNA.
Whether patients with KRAS G12C-mutant tumors and high baseline HRAS/NRAS expression have shorter duration of response to KRAS G12C inhibitors compared to those with low expression.
A prospective cohort study of 150+ patients with KRAS G12C-mutant NSCLC treated with a KRAS G12C inhibitor, measuring HRAS and NRAS mRNA and protein expression in baseline tumor biopsies via RNA-seq and IHC, and tracking time to progression and overall survival over 24 months.
Whether acquired resistance to KRAS G12C inhibitors in patients is associated with upregulation of HRAS or NRAS compared to tumors that remain sensitive.
A case-control study comparing genomic and transcriptomic profiles of tumor biopsies from 40 patients who developed resistance to KRAS G12C inhibitors (cases) versus 40 patients who remained responsive (controls), focusing on RAS isoform expression, RTK amplifications, and downstream pathway activation.
The baseline levels of HRAS and NRAS activation in tumor samples from patients with KRAS G12C-mutant cancers before treatment with KRAS G12C inhibitors.
A cross-sectional analysis of pretreatment tumor biopsies from 100 patients with KRAS G12C-mutant NSCLC, measuring active RAS-GTP levels via pull-down assays and quantifying HRAS/NRAS expression via RNA-seq to determine prevalence of co-activation.