Abstract 5427: Targeting mitochondrial protein translation in chemo-refractory triple negative breast cancer

Abstract Nearly 45% of patients with triple negative breast cancer (TNBC) treated with neoadjuvant chemotherapy have residual tumors that are correlated with worse overall survival. Residual TNBC patient-derived xenograft (PDX) tumors were found to have heightened oxidative phosphorylation (oxphos) and enhanced dependency when pharmacologically targeting the electron transport chain (ETC; PMID 30996079). We have since established in vitro models recapitulating this biology and documented pro-mitochondrial effects of conventional chemotherapies in residual cells (PMID: 36813854). Proteomic profiling of pre-treatment TNBC patient biopsies and PDX tumors matched to their responses to carboplatin (CRB), docetaxel (DTX), or the combination revealed mitochondrial translation as a top up-regulated pathway significantly associated resistance (PMID 36001024, PMID 36619972, Lei JT et al. manuscript in preparation). Furthermore, on-treatment biopsies were collected from a subset of the TNBC patient samples, and mitochondrial translation pathways were significantly elevated. Leading-edge proteins included several core mitoribosome components and the accessory protein Oxidase (Cytochrome C) Assembly 1-Like (OXA1L). OXA1L plays two critical roles in the mitochondria: 1) it promotes translation termination for the 13 mtDNA-encoded ETC proteins, and 2) it aids in inner mitochondrial membrane insertion of both mtDNA- and nDNA-encoded ETC proteins. Therefore, we hypothesize that mitochondrial translation supported by OXA1L promotes oxphos dependence in residual TNBC cells surviving conventional chemotherapies. Transient siRNA-mediated knock-down (KD) of OXA1L in TNBC cell lines reduced ETC protein levels, reduced mitochondrial ‘respirasome’ supercomplex levels, and diminished oxphos. Notably, the CRB-induced elevation of oxphos characteristic of ‘residual’ cells was significantly diminished by OXA1L KD. Concomitantly, inducible shRNA OXA1L KD cells exhibited significantly enhanced CRB sensitivity relative to control cells. These results highlight the importance of OXA1L for mitochondrial respiratory chain production and functionality. Aiming to translate these findings, we are leveraging the mitochondrial bacterial ancestry to repurpose the FDA-approved antibiotic tigecycline as a chemo-sensitizing drug based on its mitoribosome inhibitory function (PMID 25625193). We demonstrate inhibition of mitochondrial respiratory chain production, respirasome formation, and oxphos with tigecycline. While we observe minimal toxicity to TNBC cells from tigecycline alone, we observe a profound enhancement of efficacy when combined with CRB or DTX both in vitro and in an orthotopic PDX model. In summary, our data provide evidence that disrupting mitochondrial translation may be a promising approach to target mitochondrial vulnerabilities in chemo-refractory TNBC cells. Citation Format: Mariah J. Berner, Steven W. Wall, Mokryun L. Baek, Audra Lane, Allison S. Greer, Karen Wang, Lacey Dobrolecki, Bing Zhang, Jonathan T. Lei, Michael T. Lewis, Gloria V. Echeverria. Targeting mitochondrial protein translation in chemo-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 5427.