Pancreatic cancer-derived extracellular vesicles remodel the tumor microenvironment and enhance chemoresistance by delivering KRASG12D protein to cancer-associated fibroblasts

KRAS mutations are instrumental in the development and progression of pancreatic ductal adenocarcinoma (PDAC). Nevertheless, the efficacy of direct targeting of KRAS mutations to inhibit tumor development remains doubtful. It is therefore necessary to gain a deeper insight into the mechanism in which KRAS mutations influence the effectiveness of clinical treatments. In this study, KRAS G12D protein was detected in cancer-associated fibroblasts (CAFs) from clinical samples of pancreatic ductal adenocarcinoma (PDAC). In vitro experiments demonstrated that KRAS G12D protein in CAFs was not expressed from its own mutant gene but was derived from the ingestion of tumor cell-derived extracellular vesicles (EVs). The presence of KRAS G12D protein in CAFs resulted in enhanced proliferation and migration. Furthermore, KRAS G12D -containing CAFs were observed to promote tumor chemoresistance to gemcitabine treatment both in vitro and in vivo . Application of a KRAS mutation-specific inhibitor, MRTX1133, has been demonstrated to reverse chemoresistance in PDAC. Moreover, clinical data suggest that patients with KRAS mutations have poorer prognosis following adjuvant chemotherapy. These findings elucidate the mechanism by which oncogenic KRAS mutations promote cancer chemoresistance and remodel tumor environment in a non-autonomous manner, suggesting a novel strategy for targeting KRAS mutations to enhance chemosensitivity in PDAC.