Many cancers with KRAS mutations, the most commonly mutated oncogene, develop rapid resistance to targeted therapy with KRAS inhibitors. A recent study by Wantong Yao, M.D., Ph.D., Scott Kopetz, M.D., Ph.D., and Haoqiang Ying, M.D. Ph.D., and colleagues discovered that SDC1, a cell surface protein involved downstream of the KRAS-mutated pathway and associated with pancreatic cancer progression, plays a critical role in acquired resistance to KRAS inhibitors.
In preclinical models of KRAS-mutant pancreatic and colorectal cancers, SDC1 expression on the cell surface initially declined following KRAS inhibition but later re-emerged in resistant tumors. Mechanistic analyses uncovered the YAP1 oncogene as a major coordinator of SDC1 cell surface reactivation that further mediates the activation of multiple receptor tyrosine kinases and drives the development of KRAS inhibitor resistance. These findings highlight the YAP1-SDC1 axis as a key mechanism underlying this resistance and point to promising potential therapeutic vulnerability to enhance the durability of KRAS-targeted therapies. Further, the researchers suggest SDC1 may be a useful biomarker for monitoring relapse following KRAS inhibitor treatment.