Triple-negative breast cancers (TNBCs) are particularly aggressive, metastatic and resistant to chemotherapy treatments. Researchers at the University of Texas MD Anderson Cancer Center have discovered that these cells alter epigenetic programing to temporarily become drug-resistant. The resistant cells switch metabolic pathways from glycolysis to mitochondrial respiration, but a new drug targeting this pathway can thwart this evasion strategy. The study published today in Science Translational Medicine offers new hope to patients with this particularly deadly form of breast cancer.
TNBCs account for 15-20% of breast cancers. Only half of these respond to neoadjuvant chemotherapy regimens, and for those with resistant disease there are few options. “Insensitivity to chemotherapy is associated with 40-80% risk of recurrence, resulting in distant metastasis and death for most patients,” says lead author Helen Piwnica-Worms, professor of Experimental Radiation Oncology and MD Anderson
“Understanding how tumor cells become resistant will allow us to identify new targets to better treat resistant disease,” says Piwnica-Worms. “A major goal of this study was to characterize residual tumors that survived (chemotherapy) to determine whether chemotherapy resistance as due to intrinsic (genomic) and/or acquired (nongenomic) mechanisms and to determine whether resistant tumors had specific vulnerabilities that could be targeted therapeutically.”
Looking at biopsies from patient tumors, and those transplanted from patients into mouse models (patient-derived xenograft models), they examine how tumors change in response to chemotherapy treatment (AC-treatment consisting of doxorubicin (Adriamycin) and cyclophosphamide). While they find no genomic changes, there are significant epigenetic changes which are temporary—returning to normal after chemotherapy is halted. “Tumor cells in the drug-tolerant state had distinct transcriptomes, proteomes and histological features compared with untreated tumors, but gave rise to tumors with restored drug sensitivity, transcriptomes, proteomes and histological features of untreated tumors,” says Piwnica-Worms.
Among the most significant changes in chemotherapy-resistant tumors is the upregulation of the metabolic pathway for generating energy through mitochondrial respiration. “Transcriptomic analyses revealed that mitochondrial oxidative phosphorylation was the most significantly up-regulated pathway in residual tumors,” says Piwnica-Worms. Typically cells rely on glycolysis for generating energy, but this pathway is down-regulated. “Reduction of glycolysis after AC-treatment suggested that oxidative phosphorylation could serve as a compensatory metabolic pathways in residual tumors,” says Piwnica-Worms.
Indeed, increases in oxidative phosphorylation are known to contribute to therapy resistance in chronic myeloid leukemia, colon, prostate and pancreatic cancer models. “Up-regulated oxidative phosphorylation contributes to cancer stem-like cell phenotypes associated with chemo-resistance in breast cancer cells,” explains Piwnica-Worms.
As such, MD Anderson’s Therapeutic Development Division is already working on a way to block this resistance pathway. Their small-molecule IACS-010759 inhibits the mitochondrial respiration pathway and is already in phase I clinical trials for patients with acute myeloid leukemia, breast cancer and other solid malignancies. When used against chemotherapy resistant tumors, the team finds that the drug acts synergistically to delay tumor regrowth in both mouse models and in patients. “Efficacy of IACS-010759 was enhanced in the post-AC residual (tumors) compared to (untreated tumors), suggesting that a sequential regimen consisting of AC followed by IAC-010759 could prolong duration of responses to chemotherapy in TNBCs,” says Piwnica-Worms.
Such combination treatment might be augmented further with drugs that target the upstream epigenetic regulators themselves, such as HDACs 7 and 10 which orchestrate the upregulation of the mitochondrial respiration pathway. “Regulators such as these are promising contributors to the residual tumor state, and dual targeting of both metabolic and epigenetic programs may provide durable responses in TNBC,” says Piwnica-Worms.
Altogether the study significant advances our understanding of drug-resistant TNBC and provides new therapeutically actionable targets for novel combination treatments.
