Tyrosine Phosphorylation of Mitochondrial Creatine Kinase 1 Enhances a Druggable Tumor Energy Shuttle Pathway

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Mitochondrial metabolism alterations by oncogenic tyrosine kinases are crucial for tumor growth but incompletely understood.
• HER2 tyrosine kinase signaling plays a significant role in breast cancer progression.

Purpose of the Study:

• To investigate how oncogenic HER2 signaling impacts mitochondrial metabolism in breast cancer.
• To identify novel therapeutic targets within the metabolic pathways regulated by HER2.

Main Methods:

• Utilized breast cancer cell lines and patient-derived xenografts.
• Investigated the phosphorylation of mitochondrial creatine kinase 1 (MtCK1) on tyrosine 153 (Y153).
• Assessed the effects of MtCK1 knockdown and cyclocreatine treatment on cell proliferation and tumor growth.

Main Results:

• Oncogenic HER2 signaling induces Y153 phosphorylation of MtCK1 in an ABL-dependent manner.
• Y153 phosphorylation stabilizes MtCK1, enhancing the phosphocreatine energy shuttle and promoting cancer cell proliferation.
• Inhibition of the phosphocreatine energy shuttle via MtCK1 knockdown or cyclocreatine decreased proliferation in HER2+ breast cancer models.
• Combination therapy with cyclocreatine and lapatinib reduced tumor growth in a trastuzumab-resistant xenograft model.

Conclusions:

• MtCK1 Y153 phosphorylation is a key mechanism by which HER2 signaling promotes breast cancer proliferation via the phosphocreatine energy shuttle.
• Targeting the phosphocreatine energy shuttle represents a druggable metabolic vulnerability in HER2+ breast cancers, including resistant types.