Oncogenic GALNT5 confers FOLFIRINOX resistance via activating the MYH9/ NOTCH/ DDR axis in pancreatic ductal adenocarcinoma.

Abstract Chemotherapy resistance has been a great challenge in pancreatic ductal adenocarcinoma (PDAC) treatments. Current first-line chemotherapy regimens for PDAC include gemcitabine-based regimens such as AG regimen (albumin paclitaxel and gemcitabine), fluorouracil-based regiments such as FOLFIRINOX regimen (5-fluorouracil (5-FU), oxaliplatin, Irinotecan) and platinum-based regimens, especially for patients with BRCA mutations. Large amounts of work have been done on exploring the mechanism underlying resistance of gemcitabine-based and platinum-based regimens, while little research has been achieved on the mechanism of FOLFIRINOX regimens resistance in PDAC. In this study, we found that Polypeptide N-Acetylgalactosaminyltransferase 5 (GALNT5) was highly expressed in PDAC tissues and predicted poor prognosis in PDAC via the analysis of Renji tumor micro-assays (TMA), TCGA datasets, GTXs datasets, and GEO datasets. Moreover, we observed that GALNT5 promoted FOLFIRINOX resistance and cell proliferation at the same time, and proposed that GALNT5-induced oxaliplatin instead of 5-FU resistance may be the cause of FOLFIRINOX resistance. Meanwhile, GALNT5-induced FOLFIRINOX resistance was amplified by enhancing DNA damage repair instead of the usual mechanisms of 5-FU-based regimens resistance associated with cancer stem cells. Furthermore, we displayed mass spectrum and CO-immunoprecipitation (CO-IP) and found that GALNT5 interacted with MYH9, thus participating in the activation of the NOTCH pathways, resulting in hampering FOLFIRINOX-induced DNA damage. Functions of GALNT5 promoting FOLFIRINOX resistance were validated in vivo via a mouse PDAC orthotopic model. Hence, we identified GALNT5 as a vital regulator and a potential therapeutic target in FOLFIRINOX regimen resistance.