V-ATPase inhibitor for KRAS-driven cancer

A small molecule inhibitor of V-ATPase, an intracellular transmembrane complex that regulates membrane trafficking and intracellular transport processes, could help treat KRAS-driven cancers. A screen of 300 previously developed small molecules to evaluate anti-proliferative activity against several human cancer cell lines with KRAS mutations identified a compound that inhibits V-ATPase, selectively killing mutant cells with an IC50 of 0.07–0.55 µM by blocking pathways that KRAS-driven cancers rely on for survival, such as autophagy and micropinocytosis.

In a xenograft mouse model of NSCLC, the compound decreased tumor volume and increased hallmarks of autophagy inhibition compared with a vehicle control. In xenograft mouse models with four different colon cancer cell lines, the compound decreased tumor volume compared with control...