Abstract LB-250: Oncogenic activation of mitochondrial phosphocreatine energy shuttle creates a druggable metabolic liability in cancer cells

Abstract

Abstract Many important metabolic processes such as energy homeostasis, regulation of reactive oxygen species (ROS) levels, production of signaling metabolites, and synthesis of precursors for macromolecules occur in mitochondria of cancer cells. However, targeting mitochondrial metabolism in cancer has been challenging due to toxicity in normal cells, which also depend on mitochondrial metabolism. Therefore, identification of tumor specific mitochondrial metabolic alterations would be crucial to develop drugs that can selectively target cancer cells while sparing normal tissue. Here, by using targeted metabolite profiling and mitochondria-specific phospho-proteomics approach, we identified Mitochondrial Creatine Kinase (MtCK) 1 as a metabolic target in HER2+ breast cancer cells. We show that the oncogenic HER2-ABL axis stabilizes MtCK1 through tyrosine 153 (Y153) phosphorylation to activate the PCr energy shuttle pathway that transfers ATP from mitochondria to cytosol. Inhibition of the PCr energy shuttle pathway either by genetically depleting MtCK1 or by pharmacologically with a creatine analogue cyclocreatine, decreases proliferation of trastuzumab-sensitive and -resistant HER2+ cancer cells and reduces tumor growth in vivo without obvious toxicity. These findings suggest that, once ATP is produced in the mitochondria, it is equally important for breast cancer cells to transfer this energy from mitochondria to the cytosol for maintenance of various biochemical processes and tumor growth. In summary, our study reveals MtCK1 stabilization by Y153 phosphorylation as a key molecular mechanism underlying the intersection between oncogenic HER2 signaling and mitochondrial energy metabolism, which creates a druggable metabolic vulnerability in cancer. Since cyclocreatine has been used as a dietary sport supplement, cyclocreatine might be able to inhibit trastuzumab-resistant tumors with much less toxicity in patients as compared to conventional anticancer drugs. Citation Format: Taro Hitosugi, Kiran Kurmi. Oncogenic activation of mitochondrial phosphocreatine energy shuttle creates a druggable metabolic liability in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-250.