SIRT5 Promotes Chemoresistance Through Metabolic Rewiring for Nucleotide Replenishing in Refractory Triple Negative Breast Cancer

Drug resistance is the leading cause of neoadjuvant chemotherapy (NAC) failure to achieve pathological complete response (pCR) in more than 40% of patients with triple negative breast cancer (TNBC). Thus, understanding the potential drug resistance mechanisms in TNBC patients is a critical unmet clinical need. Using quantitative high-throughput metabolomic and proteomic approaches, we systematically analyzed clinicopathological, metabolic, and proteomic data profiled from NAC treatment-naive biopsy samples derived from primary TNBCs. Particularly, we identified that non-pCR TNBC primary tumors are uniquely and highly enriched in metabolic pathways for the TCA cycle and oxidative phosphorylation (OXPHOS) along with nucleotide metabolism relative to pCR TNBC tumors. In addition, sirtuin 5 (SIRT5) as a master regulator of mitochondrial metabolism is dramatically increased in non-pCR TNBC primary tumors. Of note, we found that SIRT5 is frequently overexpressed in TNBC tumors due to copy number gain and amplification. Furthermore, metabolomics and 13C-glucose tracing uncovered that SIRT5 gain of function promotes chemoresistance by diverting TCA cycle intermediates into the pentose phosphate pathway (PPP) for nucleotide replenishing. Moreover, SIRT5 knockout restores chemosensitivity to TNBC cells. We anticipate that blocking SIRT5-mediated metabolic rewiring may reverse chemoresistance in refractory TNBC patients. Zuen Ren, Kiran Kurmi, Tiziano Bernasocchi, Eric Zaniewski, Shakchhi Joshi, Garrett Lam, Chenxu (Vincent) Guo, Ilze Smidt, Preshita Dave, Agustina Maccio, Johannes Kreuzer, Gabrielle Elena Gioia, Veerle I. Bossuyt, Brian N. Dontchos, Gary X. Wang, Shinn-Huey S. Chou, Michael Lawrence, Esther Rheinbay, Laura M. Spring, Wilhelm Haas, Raul Mostoslavsky, Marcia C. Haigis, Leif W. Ellisen. SIRT5 promotes chemoresistance through metabolic rewiring for nucleotide replenishing in refractory triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4449.