Abstract 1780: Utilizing bisbiguanide compounds to disrupt metabolic heterogeneity in non-small cell lung cancer

Abstract Metastasis accounts for 90% of cancer-related deaths; however, the molecularmechanisms by which cancer cells invade and metastasize remain poorly understood. Around 80% of lung cancer patients present with metastatic disease and have only a 5%5-year relative survival. Metastases are often seeded by heterogeneous cells that invadecollectively in cellular packs. However, most studies and treatments focus on bulk cellularpopulations leaving subpopulations that drive metastasis masked. We previouslypublished on metabolic heterogeneity within collectively invading lung cancer cells andidentified the bisbiguanide compound alexidine as a disrupter of lung cancermitochondrial metabolism and invasion. To expand on these findings, we developed newbiguanides and identified promising candidates, AX-4 and AX-7. These analogs inducemitochondrial structural defects and cause metabolic rewiring. Treated lung cancer cellsexhibited reduced oxygen consumption and increased lactate production. Importantly, AX-4 and AX-7 reduced collective cell invasion, highlighting the potential of these newbiguanides to limit cancer metastasis. Taken together, we have developed new chemicaltools to disrupt mitochondrial metabolism. These tools will be useful to further parse theroles of metabolically heterogenous cancer cells on tumor growth and metastasis. Citation Format: Veronika Y. Matsuk, Christina M. Knippler, Jamie L. Arnst, Isaac E. Robinson, Tala O. Khatib, Mala Shanmugam, Thota Ganesh, Janna K. Mouw, Adam I. Marcus. Utilizing bisbiguanide compounds to disrupt metabolic heterogeneity in non-small cell lung cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 1780.