P38MAPK targeting in pancreatic ductal adenocarcinoma: Promising interventional approach for breaking drug resistance and tumor control

Pancreatic Cancer is one of the deadliest cancers and has very limited therapeutic options and a dismal prognosis with less than 11% median survival rate. Among various signaling pathways which are involved during tumor development, hyperactivation of Mitogen-Activated Protein Kinase (MAPK) is responsible for high grade angiogenesis, polarization of Tumor Associated Macrophages, unfolded protein responses and exhaustion of T cells, which together contributes towards refractory nature of pancreatic ductal adenocarcinoma (PDAC) that leads to therapeutic resistance. These concerted signaling render PDAC refractory for Cancer directed interventions. In view of pleotropic impact of MAPK, we thought whether MAPK targeting would enhance sensitivity of highly resistant PDAC cells toward gemcitabine. Supporting this hypothesis, our experimental data with PDAC tumor cells convincingly, demonstrated that p38 inhibition either pharmacologically or genetically, sensitized both Panc-1 and MIA PaCa-2 PDAC cells towards gemcitabine induced death. Interestingly, p38MAPK targeting significantly reduced the cell viability, clonogenic potential, cell migration and enhanced Apoptosis suggesting that lowering down p38MAPK is promising approach for controlling tumor burden in host. Indeed, in-silico data, corroborating in vitro findings, demonstrated that high expression of p38α (MAPK14) confer poor prognosis and disease-free survival in PDAC patients over p38MAPK low tumor patients. Taken together our data, potentially demonstrated that p38MAPK targeting is potential approach for breaking resistance of PDAC toward chemotherapy and may contribute to controlling PDAC burden effectively.

Apoptosis; Chemoresistance; Clinical correlation; Gemcitabine; PDAC; Ralimetinib; p38MAPK.