p38α Signaling Is Associated with Pancreatic Ductal Adenocarcinoma Progression and Represents a Potential Therapeutic Vulnerability.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, and approximately 15% of cases arise from intraductal papillary mucinous neoplasms (IPMNs). These precursor lesions can progress to invasive cancer through the accumulation of molecular alterations. To identify pathways associated with this transition, we performed comparative transcriptomic analyses of patient-derived IPMN and PDAC samples, followed by protein-level validation in tissue specimens and pancreatic cancer cell lines. Functional studies were conducted using the selective p38α inhibitor ralimetinib in two-dimensional cultures, three-dimensional tumorspheres, and patient-derived tumor organoids (PDTOs). Transcriptomic profiling revealed significant downregulation of the p38 pathway in IPMNs compared with PDAC, suggesting progressive pathway activation during pancreatic tumorigenesis. Immunohistochemical analyses confirmed increased phospho-activated p38α in PDAC tissues, particularly in lesions with advanced malignant features, while PDAC cell lines displayed higher levels of activated p38α than non-tumorigenic pancreatic epithelial cells. Pharmacological inhibition of p38α suppressed downstream MAPKAPK2 phosphorylation, induced apoptotic cell death, and reduced tumorsphere growth and viability. Consistently, PDTOs exhibiting elevated p38α activation showed increased sensitivity to ralimetinib treatment. Collectively, these findings identify p38α signaling as a pathway activated during PDAC progression and support further investigation of p38α-targeted therapies as a potential precision medicine strategy for pancreatic cancer.