Abstract 6768: Selective ULK1/2 inhibitors enhance KRAS pathway blockade and uncover stress-adaptive programs

Abstract KRAS is the most frequently mutated member of the RAS family in lung adenocarcinomas such as NSCLC. Although KRAS pathway inhibition can reduce tumor growth, resistance arises and thwarts its clinical potential. Prior work has suggested that the autophagy pathway is an exploitable vulnerability for mutant RAS-driven tumors. ULK1 is a central upstream regulator of the autophagy pathway, and its inhibition is a promising strategy to abrogate autophagy and improve RAS-driven tumor sensitivity to approved therapeutics. Through structure-based drug design, we generated a 7-azaindole-derived series of ULK1/2 inhibitors and characterized their structure-activity relationships. Biochemical potency was measured via ULK1/2 enzymatic assays, and intracellular target engagement was evaluated using a ULK1 NanoBRET assay. Cellular analyses were performed in KRAS mutant models using viability assays, autophagy flux measurements under starvation or treatment with MEK inhibitor. Combination studies with RAF-MEK-ERK pathway inhibitors were assessed in subcutaneous xenograft models. In order to assess the type of resistance arising from KRAS treatment, we used a combination of DNA barcode technology and transcriptomic studies to distinguish between resistance arising from clonal expansion vs adaptive, reversible survival programs consistent with drug-tolerant persister (DTP) biology. We identified potent, selective ULK1/2 inhibitors, favorable physicochemical profiles, and strong cellular target engagement. The lead analog, MR-2088, inhibited stimuli-induced autophagic flux and displayed pharmacokinetics appropriate for in vivo studies. In cells, MR-2088 enhanced the activity of MEK/ERK inhibitors and produced synergistic reductions in viability. The synergistic effect was observed in vivo. DNA barcode analysis revealed that resistance emerging after KRAS pathway inhibition was not associated with expansion of distinct clonal populations, suggesting a non-genetic adaptive mechanism. Transcriptomic profiling showed enrichment of stress-adaptive pathways, including cell-cycle remodeling, metabolic rewiring, oxidative phosphorylation, and MYC-regulated targets; patterns consistent with previously described drug-tolerant persister-like programs. This study describes a new chemotype of selective, ULK1/2 inhibitors that robustly engage the target, inhibit autophagic flux, and enhance the effectiveness of RAS pathway inhibitors. By disrupting autophagy-supported adaptive programs that arise following KRAS pathway inhibition, ULK1 blockade may enhance therapeutic responses and limit stress-induced survival states relevant to treatment tolerance. These findings support further investigation of ULK1 inhibition as a strategy to augment targeted therapy in KRAS-driven malignancies. Citation Format: Simon Bayle, Sean Chin Chan, Micheal Lamptey, Mingxiang Teng, Andrii Monastyrskyi, Derek Duckett. Selective ULK1/2 inhibitors enhance KRAS pathway blockade and uncover stress-adaptive programs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6768.