97 (PB087) - The ULK1 inhibitor ENV-201 impairs tumor growth in KRAS-driven flank xenografts as a single agent and in combination with the KRAS inhibitor adagrasib

Abstract

Background: Lung cancer is the leading cancer cause of death in the US, and non-small cell lung cancers (NSCLCs) account for 85% of those cases. Among NSCLCs, mutations resulting in ectopic activation of the RAS signal transduction pathway account for at least a quarter of cases, and the activating KRASG12Cmutation is found in 11% of all NSCLC patient samples. When treated with RAS pathway-inhibiting therapeutics, KRAS-driven tumors have been shown to become dependent on autophagy for continued survival. Simultaneous targeting of both the RAS pathway and autophagy therefore presents an opportunity to block multiple mechanisms of tumor growth and survival. Materials and methods: We have demonstrated the added benefit of KRAS inhibition and autophagy inhibition in an animal model, using the NCI-H2122 cell line (homozygous for the activating KRASG12C mutation) as flank xenografts in NOD/SCID mice. ENV-201 is a selective and potent antagonist of the autophagy-initiating kinase, ULK1, one which also inhibits the related ULK2. Mice were treated via daily oral dosing of (1) vehicle, (2) ENV-201 (20 mg/kg), (3) the KRASG12C-specific inhibitor adagrasib (Mirati Therapeutics, 25 mg/kg), or (4) combination of both ENV-201 and adagrasib at the same doses. Treatment lasted 30 days, body weight was monitored daily, and tumor size was measured three times a week. All animal work was carried out at and met necessary approvals at Crown Bioscience. Results: Both ENV-201 and adagrasib treatments resulted in significant tumor growth inhibition when either drug was used as a single agent (32% or 55% TGI, respectively). Significant additive tumor growth inhibition (78%) was also observed when animals were treated with both drugs in combination. Conclusions: ENV-201-mediated ULK1 inhibition thus shows promise as both a single agent or in combination with a growth factor/RAS/MAPK pathway-targeting cancer treatment. Conflict of interest: Corporate-sponsored Research: All authors are employees of Endeavor BioMedicines.