Pancreatic cancer: emerging small molecule pharmacotherapies

INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal solid malignancies, driven by aggressive tumor biology, therapeutic resistance, and activation of oncogenic KRAS. Despite advances in chemotherapy, effective targeted treatment options have been lacking, positioning PDAC as an unmet medical need in oncology. AREAS COVERED: This review examines progress in small-molecule pharmacotherapy for PDAC, with a focus on emerging KRAS-directed agents, including G12D-selective inhibitors and alternative KRAS-targeting strategies, as well as downstream inhibition of MAPK and PI3K signaling. In addition, the review discusses adaptive vulnerabilities that sustain KRAS-driven tumors, including non-oncogene addiction to cell-cycle regulation, DNA damage response pathways, transcriptional plasticity, and metabolic rewiring.The analysis integrates evidence from preclinical studies and early-phase clinical trials identified through a comprehensive literature search of PubMed and ClinicalTrials.gov for English-language articles published between January 2005 and December 2025, using keywords related to PDAC and small-molecule pharmacotherapy. EXPERT OPINION: The field is transitioning from single-pathway inhibition toward rational, biomarker-guided combination strategies aimed at disabling adaptive survival networks rather than KRAS signaling alone. Future success of PDAC pharmacotherapy will depend on improved patient selection, validation of predictive biomarkers, and innovative clinical trial designs capable of balancing efficacy with the toxicity of multi-agent regimens.