Triple-negative breast cancer (TNBC) is a molecularly heterogeneous group of diseases defined by the lack of estrogen receptor (ER), progesterone receptor (PR) and absence of human epidermal growth factor receptor-2 (HER2) amplification. Consequently, TNBCs are impervious to therapies commonly used in other breast cancer subtypes and treatment options are largely limited to conventional genotoxic chemotherapy agents including doxorubicin. The long-term prognosis for TNBC patients with residual disease after chemotherapy is poor and a need exists to identify rational combination therapy approaches to improve the efficacy of chemotherapy for treating TNBC.
Recent studies suggest that reprogramming of cell metabolism is a component of the highly coordinated response to genotoxic stress. However, the metabolic response to clinically relevant genotoxic chemotherapy agents is poorly understood. Using in vitro and in vivo metabolic profiling of TNBC cells, we have identified the spectrum of metabolic reprogramming events induced when TNBC cells are exposed to chemotherapy. I will describe how therapy-induced adaptive reprogramming of de novo pyrimidine synthesis and mevalonate metabolism limits the therapeutic efficacy of chemotherapy for the treatment of TNBC. Moreover, I will demonstrate how clinically approved inhibitors of these metabolic pathways can be leveraged to sensitize TNBC cells to chemotherapy.
Collectively, our studies demonstrate that adaptive reprograming of cell metabolism, induced in response to chemotherapy exposure, represents a vulnerability that can be harnessed and exploited to improve the anticancer activity of genotoxic chemotherapy agents for the treatment of TNBC.