Mitochondrial Protein Offers Potentially Novel Target for HER2+ Breast Cancer

A new laboratory study has shed some light on how mitochondrial metabolism is altered in breast cancer, and how combining treatments for HER2-positive breast cancer with a creatine analog can slow cell proliferation in this malignancy.

“Based on the concept that oncogene activation may upregulate mitochondrial metabolic pathways to meet cellular bioenergetic and biosynthetic needs in cancer cells as compared with normal cells, several drugs targeting mitochondrial metabolism are currently being assessed in clinical trials as potential anticancer agents,” wrote study authors led by Taro Hitosugi, PhD, of the Mayo Clinic in Rochester, Minnesota. “However, targeting mitochondrial metabolism in cancer has been challenging due to toxicity in normal cells, which also depend on mitochondrial metabolism. Therefore, identifying tumor-specific mitochondrial metabolic alterations could aid in the design of drugs that can selectively target cancer cells while sparing normal tissue.”

The researchers used targeted metabolite profiling and organelle-specific phospho-proteomic analysis to identify metabolic targets of HER2 signaling in mitochondria. In a paper published in Cell Metabolism, they found that HER2 signaling induces phosphorylation of mitochondrial creatine kinase 1 (MtCK1), a protein that facilitates the “phosphocreatine energy shuttle” on tyrosine 153 (Y153). Phosphorylation of Y153 is commonly upregulated in HER2-positive breast cancer.

“Although the HER2-directed monoclonal antibody trastuzumab has substantial activity against HER2-positive breast cancer, intrinsic and acquired resistance to this agent remain problematic, underscoring the need to develop new therapeutic approaches,” the researchers wrote.

They then created cell lines in which MtCK1 was depleted, to determine its role in proliferation of trastuzumab-resistant cancer cells. They found that MtCK1 depletion did in fact reduce cell proliferation, which led to a question of whether targeting the phosphocreatine energy shuttle might offer some therapeutic benefit. They tested a creatine analog known as cyclocreatine, and again found they could reduce cell proliferation; importantly, normal breast epithelial cells were not affected by the agent, suggesting this approach may have selective antitumor activity in HER2-positive breast cancer.

Finally, they combined cyclocreatine with the anti-HER2 targeted agent lapatinib to examine the effects on trastuzumab-resistant HER2-positive breast cancer cells. Combined treatment with the two agents was significantly more effective than either agent administered alone.

“Overall, these preclinical studies suggest that the phosphocreatine energy shuttle may be a druggable metabolic dependency in HER2-positive breast cancer,” the authors concluded.