Culprits of PDAC resistance to gemcitabine and immune checkpoint inhibitor: Tumour microenvironment components

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and lethal cancer with a dismal five-year survival rate of 11%. Despite remarkable advancements in cancer therapeutics, PDAC patients rarely benefit from it due to insurmountable treatment resistance. Notably, PDAC is pathologically characterized by an extensive desmoplastic reaction and an extremely immunosuppressive tumour microenvironment (TME). The PDAC TME consists of cell components (e.g., tumour, immune and stromal cells) and noncellular components (e.g., extracellular matrix), exhibiting high complexity and their interplay resulting in resistance to chemotherapeutics and immune checkpoint inhibitors. In our review, we shed light on how crosstalk of complex environmental components modulates PDAC drug resistance, and we summarize related clinical trials. Moreover, we extend our discussion on TME exploration and exosome analysis, providing new insights into clinical applications, including personalized medicine, disease monitoring and drug carriers.

Concurrent inhibition of pBADS99 synergistically improves MEK inhibitor efficacy in KRASG12D-mutant pancreatic ductal adenocarcinoma

“…Lack of specific and accessible early-stage biomarkers, therapy resistance, and consequent recurrence of PDAC demand novel and potent strategies to improve patient survival [ 48 , 49 ]. As the most frequently mutated RAS gene (84%) in human cancer [ 9 , 50 ], KRAS mutations are associated with a worse prognosis in PDAC (90%), colorectal cancer (50%), non-small cell lung cancer (30%) and other human malignancies [ 6 ].…”

Recent progress in mRNA cancer vaccines

“…Personalized mRNA vaccines offer promising treatments for cancers resistant to current immunotherapy, such like pancreatic ductal adenocarcinoma (PDAC), which shows resistance to immune checkpoint inhibitors (ICIs). 135 The abundance of neoantigens in pancreatic cancer makes neoantigen-based mRNA vaccines a viable therapeutic strategy. BNT122 employs mRNA to express 20 novel antigens in PDAC patients.…”

Review and Application of Integrin Alpha v Beta 6 in the Diagnosis and Treatment of Cholangiocarcinoma and Pancreatic Ductal Adenocarcinoma

“…It is urgent to continue studying the drug mechanism and developing more effective projects to overcome drug resistance. 158 Reader 130 administered a combination of gemcitabine and 264RAD (an integrin αvβ6 inhibitor) to tumor-bearing mice. The combination treatment resulted in significantly smaller or even complete tumor disappearance.…”