Harnessing novel agents to target KRAS-driven pathways in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy in which activating KRAS mutations, present in more than 90% of tumors, constitute the principal oncogenic driver. Advances in structural biology have enabled the pharmacologic targeting of KRAS, a protein historically regarded as 'undruggable,' with allele-specific, pan-KRAS, and pan-RAS inhibitors being developed and clinically evaluated.

This review covers the KRAS signaling pathway, the development and current data for allele-specific inhibitors (KRAS G12C and G12D), pan-KRAS/multi-KRAS inhibitors, and pan-RAS (OFF- and ON-state) inhibitors as well as mechanisms of adaptive and acquired resistance and strategies to overcome them and additional modalities including targeted protein degraders (PROTACs), RNA interference, and KRAS neoantigen vaccines. A literature search was performed in PubMed/MEDLINE and ClinicalTrials.gov, supplemented by abstracts from major oncology congresses (ASCO, AACR, ESMO).

The management of PDAC is shifting from empirical chemotherapy toward biomarker-driven RAS inhibition, and the near-doubling of overall survival with the pan-RAS inhibitor daraxonrasib in the phase III RASolute 302 trial represents a critical advance in a disease where progress has historically been incremental. The central challenge is to optimize the therapeutic window, depth, and durability of RAS suppression, anticipating resistance while defining the optimal sequencing and combination of allele-specific, pan-KRAS, and pan-RAS agents.