Abstract 1802: Melanoma addiction to GCDH

Abstract Rewiring of metabolic pathways often underlies the malignant state, including melanoma. In our previous studies we have demonstrated melanoma addiction to Gutaryl Co-dehydrogenase (GCDH), an enzyme in the lysine catabolism pathway. Our studies revealed that blocking GCDH activity in melanoma, but not colon, lung or breast cancer cells, led to cell death which abolished growth both in culture and in vivo. Important cellular component which was found to mediate melanoma addiction to GCDH was the transcription factor NRF2, which exhibited tumor suppressor function upon GCDH inhibition. Notably, coinciding with NRF2 tumor suppressor role seen upon GCDH inhibition was its glutarylation, a post translational modification which acquired NRF2 stability and ability to induce transcription of ATF4, ATF3 and CHOP which led to extensive cell death program. Knockdown of NRF2, ATF3 or DTHDK-1 effectively blocked the cell death phenotype seen upon GCDH knockdown. Analyses of patient data confirmed that low GCDH expression coincided with prolonged survival of melanoma but not colon, breast or prostate cancer patients. These findings led us to perform an unbiased screen to identify cellular components, which underlie melanoma addiction to GCDH. The results of this analysis will be discussed. Citation Format: Namratha Nadig, Sachin Verma, Ze'ev A. Ronai. Melanoma addiction to GCDH [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(6_Suppl):Abstract nr 1802.