SRC at the crossroads of KRAS inhibitor resistance: Mechanisms and therapeutic opportunities.

Kirsten rat sarcoma (KRAS) mutations are among the most common oncogenic drivers in human cancers, particularly in non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and pancreatic ductal adenocarcinoma (PDAC). The development of allele-specific KRAS inhibitors, especially those targeting the KRASG12C variant, represents a landmark achievement in precision oncology. Yet their therapeutic benefit is often transient, as tumors rapidly develop seemingly heterogeneous resistance mechanisms. Increasing evidence implicates SRC, a non-receptor tyrosine kinase frequently hyperactivated in KRAS-mutant cancers, as a central regulator of resistance. This review integrates current evidence supporting SRC's role in mediating diverse resistance pathways, including mitogen-activated protein kinase (MAPK) reactivation, transcriptional/epigenetic reprogramming, metabolic adaptation, multidrug resistance, cell death evasion, and remodeling of the tumor microenvironment. We also critically examine the shortcomings of early-generation SRC inhibitors in solid tumors and highlight emerging therapeutic avenues such as next-generation inhibitors, proteolysis-targeting chimera (PROTAC) degraders, and biomarker-guided combination strategies. By connecting molecular insights with preclinical and clinical findings, this review positions SRC as a therapeutically actionable vulnerability in KRAS-driven cancers and outlines a translational framework for overcoming drug resistance.