PanKRAS

PanKRAS is a term used in cancer research to describe strategies intended to inhibit KRAS signaling across multiple KRAS mutations or across the KRAS protein family. It contrasts with mutation-specific approaches that target a single KRAS variant, such as G12C, and seeks to address the broad spectrum of oncogenic KRAS alterations found in tumors. KRAS is a small GTPase that acts as a molecular switch regulating cell growth and survival; activating mutations lock KRAS in a signaling-competent state, driving many cancers including pancreatic, colorectal, and lung cancer. The concept of panKRAS aims to extend therapeutic reach beyond the subset of tumors harboring a single actionable mutation.

Strategies include inhibitors that bind shared KRAS features such as the switch II pocket to target multiple mutant forms; compounds that interfere with nucleotide exchange by affecting SOS1/GEF interactions; approaches to mislocalize KRAS at the membrane; and degraders that promote KRAS destruction. Some programs also pursue pan-RAS inhibition across all RAS family members rather than a single isoform.

Clinical progress is ongoing, with numerous preclinical candidates and early-phase trials exploring panKRAS modalities. Challenges include achieving selectivity for mutant KRAS over wild-type RAS, managing potential toxicities from widespread RAS pathway inhibition, tumor heterogeneity, and the emergence of resistance mechanisms. The field remains exploratory, and no panKRAS therapy has yet gained regulatory approval.