Neoadjuvant chemotherapy (NACT) used for
triple negative breast cancer (TNBC) eradicates
tumors in ~45% of patients. Unfortunately, TNBC patients with substantial
residual cancer burden have poor
metastasis free and overall survival rates. We previously demonstrated mitochondrial oxidative phosphorylation (OXPHOS) was elevated and was a unique therapeutic dependency of residual TNBC cells surviving NACT. We sought to investigate the mechanism underlying this enhanced reliance on mitochondrial metabolism. Mitochondria are morphologically
plastic organelles that cycle between fission and fusion to maintain mitochondrial integrity and metabolic homeostasis. The functional impact of mitochondrial structure on metabolic output is highly context dependent. Several
chemotherapy agents are conventionally used for
neoadjuvant treatment of TNBC patients. Upon comparing mitochondrial effects of conventional
chemotherapies, we found that
DNA-damaging agents increased mitochondrial elongation, mitochondrial content, flux of
glucose through the TCA cycle, and OXPHOS, whereas
taxanes instead decreased mitochondrial elongation and OXPHOS. The mitochondrial effects of
DNA-damaging
chemotherapies were dependent on the mitochondrial inner membrane fusion
protein optic atrophy 1 (OPA1). Further, we observed heightened OXPHOS, OPA1
protein levels, and mitochondrial elongation in an orthotopic patient-derived xenograft (PDX) model of residual TNBC. Pharmacologic or genetic disruption of mitochondrial fusion and fission resulted in decreased or increased OXPHOS, respectively, revealing longer mitochondria favor oxphos in TNBC cells. Using TNBC cell lines and an in vivo PDX model of residual TNBC, we found that sequential treatment with
DNA-damaging
chemotherapy, thus inducing mitochondrial fusion and OXPHOS, followed by MYLS22, a specific inhibitor of OPA1, was able to suppress mitochondrial fusion and OXPHOS and significantly inhibit regrowth of
residual tumor cells. Our data suggest that TNBC mitochondria can optimize OXPHOS through OPA1-mediated mitochondrial fusion. These findings may provide an opportunity to overcome mitochondrial adaptations of chemoresistant TNBC.