Enhancing Cancer Treatment Efficacy by Combining MYC Inhibitors with Metabolic Drugs

Recent research from Northwestern Medicine highlights a promising new strategy to improve cancer therapies targeting the MYC oncogene, which is implicated in over half of all human cancers and often contributes to treatment resistance. The study, published in Science Advances, demonstrates that combining MYC inhibitors with metabolic drugs could significantly enhance treatment outcomes for aggressive cancers.

The researchers focused on a novel MYC inhibitor, MYCi975, and employed a genome-wide CRISPR screen in MYC-dependent prostate cancer cell lines. This approach aimed to identify genes that, when suppressed, increased the cancer cells' sensitivity to MYC inhibition. Interestingly, the study revealed that mitochondrial complex I genes play a crucial role in this process. MYC fuels tumor growth partly by boosting mitochondrial function and energy production, primarily through oxidative phosphorylation.

When MYCi975 inhibits these mitochondrial genes, it impairs the cells’ energy generation, leading to metabolic stress. To counteract this, cancer cells upregulate mitochondrial complex I genes as a compensatory mechanism. The team found that targeting these upregulated genes with the FDA-approved diabetes drug metformin, known for its ability to inhibit mitochondrial complex I, causes cancer cells to collapse under metabolic strain.

This combination approach—using MYC inhibitors alongside metabolic drugs like metformin—offers a rapid, translatable option to improve therapy for MYC-driven cancers. Furthermore, the study suggests that the levels of mitochondrial complex I genes could serve as biomarkers to predict which tumors would respond best to this treatment approach.

Dr. Abdulkadir, the senior author of the study, emphasizes the importance of this discovery: "If a tumor lacks these mitochondrial complex I genes, it may respond even better to MYC inhibition. This opens the door to personalized treatment strategies that consider the tumor's metabolic profile."

Overall, this research underscores an innovative therapeutic strategy that combines emerging MYC inhibitors with well-established metabolic drugs to potentially increase effectiveness and overcome resistance in difficult-to-treat cancers.