Advances in Novel Targeted Therapies for Pancreatic Adenocarcinoma

J Gastrointest Cancer. 2025 Jan 6;56(1):38. doi: 10.1007/s12029-024-01149-w.

Abstract

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with limited therapeutic options and poor prognosis. Recent advances in targeted therapies have opened new avenues for intervention in PDAC, focusing on key genetic and molecular pathways that drive tumor progression.

Methods: In this review, we provide an overview on advances in novel targeted therapies in pancreatic adenocarcinoma.

Results: Here, we explore the latest development in targeting the KRAS pathway, a historically "undruggable" target crucial to PDAC pathogenesis. Strategies to inhibit KRAS include direct KRAS-targeted therapies, modulation of upstream and downstream signaling, KRAS-specific siRNA, and novel combination therapies integrating KRAS inhibitors with immune checkpoint blockade, PARP inhibitors, chemotherapy, CDK4/6 inhibitors, and autophagy modulators. Beyond KRAS, emerging targets such as NRG1 fusions, NTRK/ROS1 fusions, RET alterations, and the PRMT5/CDKN2A/MAT2A axis, along with EGFR and Claudin18.2 inhibitors, are also discussed as promising therapeutic strategies. Additionally, the review highlights novel approaches for microsatellite instability-high (MSIH) PDAC and emerging therapies, including adoptive cell therapies (CAR-T, TCR, TIL), cancer vaccines, and strategies to modify the tumor microenvironment.

Conclusion: Overall, the rapid evolution of targeted therapies offers renewed optimism in the fight against pancreatic cancer, a malignancy with historically poor outcomes.

Keywords: CAR T-cell therapy; Novel targeted therapies; Pancreatic adenocarcinoma (PDAC); Proteolysis-targeting chimeras (PROTACs).

Publication types

  • Review

MeSH terms

  • Carcinoma, Pancreatic Ductal* / drug therapy
  • Carcinoma, Pancreatic Ductal* / genetics
  • Carcinoma, Pancreatic Ductal* / pathology
  • Humans
  • Molecular Targeted Therapy* / methods
  • Pancreatic Neoplasms* / drug therapy
  • Pancreatic Neoplasms* / genetics
  • Pancreatic Neoplasms* / pathology
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • Tumor Microenvironment / drug effects

Substances

  • KRAS protein, human
  • Proto-Oncogene Proteins p21(ras)