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New-generation KRAS G12C inhibitors demonstrate enhanced activity in both peripheral and central nervous system malignancies. Frontier Medicines' pyridopyrimidines and Novartis's spiro-indazole inhibitor (opnurasib) overcome resistance mechanisms by targeting both GDP- and GTP-bound KRAS states. Their blood-brain barrier permeability and synergy with immune checkpoint inhibitors represent a transformative advance for KRAS-driven cancers, especially metastatic nonsmall cell lung cancer (NSCLC).
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Renner et al. (2025) studied this question.
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