Copper Transporter 1-Mediated Deregulation of Copper Homeostasis Impacts MYC and Oxidative Phosphorylation Pathways and Increases the Sensitivity of Tumor Cells to Complex I Inhibitors

Certain tumors are dependent on copper for proliferation, metastasis, and energy production, making them particularly susceptible to copper depletion. Altering copper homeostasis has emerged as a promising strategy for treating these cancers. Previously, we synthesized novel compounds, JR4-187 (JR4) and JR5-26B (JR5), which demonstrated copper-dependent in vivo efficacy. RNA-seq analysis revealed that JR4 treatment in colon cancer cells leads to a marked downregulation of oxidative phosphorylation and MYC-targeted genes. Both JR4 and JR5 reduce MYC and NDUFS7 protein levels. Additionally, JR4 and JR5 increase tumor cell sensitivity to complex I inhibitors, including AGB-374, a novel NDUFS7 inhibitor that we developed. AGB-374 exhibited in vivo efficacy when administered orally, both as a single agent and in combination with JR5, in a mouse model of colon cancer. Our findings indicate a significant functional relationship between CTR1 and NDUFS7, providing a foundation for the development of new cancer therapies.