J Dig Cancer Res.  2025 Apr;13(1):52-64. 10.52927/jdcr.2025.13.1.52.

Targeted Therapy for Pancreatic Cancer: Focus on KRAS

• Keum J
• Lee SH

• KMID: 2567139
• DOI: http://doi.org/10.52927/jdcr.2025.13.1.52

Abstract

Pancreatic cancer is among the most aggressive malignancies, with a 5-year overall survival rate of approximately 10%. Despite the establishment of gemcitabine- and fluoropyrimidine-based combination chemotherapy as the standard of care, therapeutic outcomes remain poor due to inherent and acquired resistance to chemotherapy. In recent years, the development of targeted therapies has emerged as a promising treatment modality, driven by advances in molecular biology and genomic profiling. Notably, mutations in the KRAS gene—detected in nearly 90% of pancreatic cancer cases—are recognized as key oncogenic drivers, contributing significantly to tumor initiation, progression, and therapeutic resistance. As such, KRAS has become a focal point for therapeutic intervention. Strategies aimed at targeting KRAS include (1) direct inhibitors of specific KRAS mutations, (2) inhibitors of upstream regulators such as SOS1 and SHP2, and (3) inhibitors of downstream effectors within the RAS signaling cascade. Given the challenges posed by compensatory signaling mechanisms that reduce the efficacy of direct KRAS inhibitors, ongoing research is exploring alternative approaches such as pan-KRAS inhibitors, combination regimens that pair KRAS inhibitors with cytotoxic chemotherapy, and dualtarget strategies involving upstream and downstream signaling components. For the subset of patients (approximately 10%) with wild-type KRAS, the U.S. Food and Drug Administration has approved targeted therapies for tumors harboring specific rare genetic alterations, including NTRK, BRAF, NRG1, ALK, ROS1, RET, and those with mismatch repair deficiency or microsatellite instability-high status. Furthermore, poly(ADP-ribose) polymerase inhibitors have shown clinical benefit in patients with germline or somatic mutations in DNA damage repair genes such as BRCA1, BRCA2, and PALB2.

Keyword

Pancreatic neoplasms; KRAS; Drug therapy; Targeted therapy