KRAS-Wild Pancreatic Cancer—More Targets than Treatment Possibilities?

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a five-year survival rate of 3–15% and limited effective treatment options for most patients. Approximately 5–10% of cases are wild-type KRAS and are more likely to harbor rare alterations, including gene fusions involving anaplastic lymphoma kinase (ALK), ROS Proto-Oncogene 1 (ROS1), neurotrophic tyrosine receptor kinase (NTRK), Rearranged During Transfection (RET), Fibroblast Growth Factor Receptor (FGFR), or Neuregulin 1 (NRG1) genes, as well as germline mutations in DNA repair genes. This review integrates current evidence on the prevalence, molecular profile, and clinical significance of gene fusions, amplification, and somatic/germline mutations in PDAC, with a particular focus on the wild-type KRAS subgroup. Clinical trial data and case reports indicate that these alterations can enhance patient susceptibility to targeted therapies. Currently, selpercatinib, larotrectinib, and repotrectinib are approved by the FDA for the treatment of certain solid tumors harboring specific gene fusions. Recent studies on zenocutuzumab resulted in the FDA-accelerated approval for NGR1 fusion-positive NSCLC and PDAC. Germline mutations may specifically increase responsiveness to poly(ADP-ribose) polymerase (PARP) inhibitors or platinum-based treatments. Comprehensive genomic profiling, incorporating fusion detection and germline testing, is essential to identify patients who may benefit from precision-based approaches.