Abstract 1256: A novel therapeutic approach to overcome metabolic reprogramming in lung cancer.

Abstract Lung cancer remains the leading cause of cancer-related deaths. Genomic studies have identified frequent mutations in subunits of the SWI/SNF chromatin remodeling complex, particularly in SMARCA4 and ARID1A, in non-small cell lung cancer, with mutations occurring in up to 33% of advanced cases. Previously we have shown that SMARCA4-mutant lung cancers are highly dependent on oxidative phosphorylation (OXPHOS). However, OXPHOS inhibitors as single agents have failed to show substantial efficacy in clinical trials. Thus, like other therapeutics aimed at cancer metabolism, the most feasible route for further development of OXPHOS inhibitors is through rational combination strategies. To this end, we undertook a functional genomics screen to identify combination strategies by utilizing a CRISPR-Cas9 library targeting genes with FDA approved therapeutics in genetically defined lung cancer models. Importantly, we utilized very low doses of the OXPHOS inhibitor IACS-10759 that are known to be well-tolerated in patients. Among our top hits was ROCK1/2. We show that Belumosudil, a clinically-utilized ROCK inhibitor known for its robust safety and tolerability profile, exhibits profound synergistic anti-tumor activity when combined with IACS-10759 in cell lines as well as in multiple mouse xenograft and human PDX models. Mechanistically, metabolic profiling reveals that the combination of ROCK and OXPHOS inhibition triggers bioenergetic stress and cell cycle arrest. This is primarily attributed to the inhibition of the adaptive increase in glycolysis that occurs following OXPHOS inhibition by ROCK, via suppression of GLUT1-mediated glucose uptake. Through quantitative proteomics, phospho-proteomics and kinase motif analysis, we identified several direct ROCK substrates including PPP1R12A and PPP1R12C that play critical roles in actin cytoskeleton regulation and glucose transport. Taken together, we identified the mechanistic underpinnings of a highly synergistic combination strategy that overcomes adaptive metabolic reprograming which has been a central challenge in the successful development of therapeutics targeting cancer metabolism. Citation Format: Nicholas Blazanin, Xiaobing Liang, Yonathan Lissanu. A novel therapeutic approach to overcome metabolic reprogramming in lung cancer 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 1256.