Unravelling Resistance: Integrating Metabolism, Epigenetics, Immunology, and Proteostasis in Strategies against Kirsten Rat Sarcoma Viral Oncogene Homolog-mutant Colorectal Cancer

Colorectal cancer (CRC) has a high incidence and mortality rate globally, with approximately 40% of patients harboring Kirsten rat sarcoma viral oncogene homolog (<i>KRAS</i>) mutations. Patients with <i>KRAS</i> mutations exhibit poorer prognoses compared to those with <i>KRAS</i> wild-type tumors, often showing resistance to targeted therapies and chemotherapy. There is an acute need for innovative therapeutic strategies, particularly as KRAS^G12C inhibitors have been approved by the U.S. Food and Drug Administration (FDA) for second-line therapy in treating non-small cell lung cancer (NSCLC). Yet, their efficacy in CRC remains suboptimal due to the emergence of drug resistance. Current research on KRAS inhibitor resistance in CRC focuses mainly on single biological processes, leaving the complex interplay between cellular systems underexplored. This review synthesizes evidence across four key dimensions - metabolism, epigenetics, immunology, and proteostasis - to reveal multidimensional mechanisms of resistance. How these interconnected pathways work in synergy with signaling aberrations, genetic alterations, and translational modifications to reinforce resistance was investigated. The research also integrates recent advances in multi-targeted strategies, including combinations of KRAS inhibitors with metabolic or epigenetic modulators or immune checkpoint blockade. These findings provide potential strategies for overcoming resistance in <i>KRAS</i>-mutant CRC, addressing a critical gap in precision oncology.