Interplay between MAP kinases and tumor microenvironment: Opportunity for immunotherapy in pancreatic cancer

Pancreatic Ductal Adenocarcinoma (PDAC), commonly called pancreatic cancer, is aggressive cancer usually detected at a late stage, limiting treatment options with modest clinical responses. It is projected that by 2030, PDAC will be the second most common cause of cancer-related mortality in the United States. Drug resistance in PDAC is common and significantly affects patients' overall survival (OS). Oncogenic KRAS mutations are nearly uniform in PDAC, affecting over 90% of patients. However, effective drugs directed to target prevalent KRAS mutants in pancreatic cancer are not in clinical practice. Accordingly, efforts are continued on identifying alternative druggable target(s) or approaches to improve patient outcomes with PDAC. In most PDAC cases, the KRAS mutations turn-on the RAF-MEK-MAPK pathways, leading to pancreatic tumorigenesis. The MAPK signaling cascade (MAP4K→MAP3K→MAP2K→MAPK) plays a central role in the pancreatic cancer tumor microenvironment (TME) and chemotherapy resistance. The immunosuppressive pancreatic cancer TME is another unfavorable factor affecting the therapeutic efficacy of chemotherapy and immunotherapy. The immune checkpoint proteins (ICPs), including CTLA-4, PD-1, PD-L1, and PD-L2, are critical players in T cell dysfunction and pancreatic tumor cell growth. Here, we review the activation of MAPKs, a molecular trait of KRAS mutations and their impact on pancreatic cancer TME, chemoresistance, and expression of ICPs that could influence the clinical outcomes in PDAC patients. Therefore, understanding the interplay between MAPK pathways and TME could help to design rational therapy combining immunotherapy and MAPK inhibitors for pancreatic cancer treatment.