Molecular Mechanisms of Resistance to KRAS^G12C Inhibitors in NSCLC- From Genomic Evolution to TME Adaptation

The clinical breakthrough achieved with KRAS^G12C inhibitors is limited in therapeutic response by the remarkable adaptive capacity of KRAS-mutant tumors. The drug resistance emerges through a dynamic interplay between tumor intrinsic and micro-environmental mechanisms. At the cellular level, there may be a rebound of KRAS-dependent signaling due to secondary alterations within mutant KRAS or there may be the acquisition of co-mutations followed by activation of KRAS-independent bypass pathways to drive the therapeutic escape. The hypoxic tumor microenvironment (TME) also evolves to support cancer cell growth and exerts a critical influence on therapeutic efficacy. The desmoplastic stromal remodelling imposes substantial barrier to drug delivery and limits effective target engagement. Additionally, as a consequence of various genotoxic assaults, the dependence on DNA damage response (DDR) pathways increases under oncogenic and therapeutic pressure which is supported by aberrant expression of DDR proteins. KRAS stability and signaling output are also reinforced by proteostasis networks and endoplasmic reticulum stress responses, which collectively sustain tumor fitness during pharmacologic inhibition. In this Review, we synthesize emerging insights into the multi-layered mechanisms that constrain the efficacy of KRAS^G12C targeted therapies and discuss evolving therapeutic strategies designed to overcome adaptive resistance in KRAS mutant malignancies.