In recent years, scientists have made significant progress in cancer treatment, particularly in the development of inhibitors targeting the MYC gene. The MYC gene plays a key role in many aggressive cancers, with its aberrant activation closely linked to tumor growth and treatment resistance. Approximately 30% of cancer patients have abnormal MYC expression, making MYC a key target for cancer treatment. However, due to its complex structure and function, MYC has long been considered an undruggable target. Technological advances have enabled several MYC inhibitors to enter clinical trials, but their efficacy still requires further improvement. Therefore, exploring combination therapy strategies that synergize with MYC inhibitors is poised to become a hot topic in cancer research.
Recently, in a research paper titled "Impaired mitochondrial metabolism is a critical cancer vulnerability for MYC inhibitors," published in the international journal Science Advances, scientists from Northwestern University Feinberg School of Medicine and other institutions, using genome-wide CRISPR screening, revealed a synergistic effect between MYC inhibitors and mitochondrial metabolism, providing new insights into cancer treatment.
In the article, the researchers found that when MYC is inhibited, the destruction of mitochondrial complex I significantly enhances the sensitivity of tumor cells to MYC inhibitors. This discovery not only provides theoretical support for the clinical application of MYC inhibitors, but also provides a scientific basis for the development of new combination treatment options. The MYC gene plays a wide range of roles in cancer, including cell cycle regulation, apoptosis, DNA replication, protein synthesis and metabolism. Among them, MYC is particularly critical in regulating cellular metabolism. Although the role of MYC in glycolysis has been widely studied, its regulatory mechanism for mitochondrial oxidative phosphorylation (OXPHOS) is still unclear. In order to systematically identify pathways that can enhance the efficacy of MYC inhibitors, the researchers used a small molecule MYC inhibitor called MYCi975 and performed whole-genome CRISPR screening.
Figure 1. Genome-wide CRISPR screen identifies mitochondrial complex I as synthetic lethal with MYC inhibition. (Yang W, et al., 2025)
The study involved the mouse prostate cancer cell line MycCaP and various human prostate cancer cell lines. The researchers employed CRISPR technology to knock out specific genes to investigate their effects on sensitivity to MYC inhibitors. They employed a variety of techniques, including CRISPR gene editing, RNA sequencing, metabolomics analysis, flow cytometry, and animal model experiments. First, CRISPR screening revealed that disruption of mitochondrial complex I (MCI) exhibited the most significant synergistic effect with MYC inhibitors. Gene knockout and drug inhibition experiments confirmed that disruption of MCI significantly enhanced the efficacy of MYC inhibitors. Metabolomics analysis also revealed that the combined use of MYC inhibitors with mitochondrial metabolic inhibitors induces metabolic changes in tumor cells, particularly a significant increase in purine metabolism.
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The results indicate that the combination of MYC inhibitors with mitochondrial complex I inhibitors significantly enhances the killing effect on tumor cells. In in vitro studies, this combination therapy reduced tumor cell survival. In animal models, the combination therapy also inhibited tumor growth. Furthermore, this combination therapy significantly altered the metabolic profile of tumor cells, particularly increasing uric acid production, which may be associated with enhanced anti-tumor immune responses.
In summary, this study reveals a synergistic effect between MYC inhibitors and mitochondrial metabolism inhibitors, providing a new strategy for cancer treatment. Future studies will further investigate the clinical potential of this combination therapy and assess its efficacy in various cancer types.
Reference
Yang W, et al. Impaired mitochondrial metabolism is a critical cancer vulnerability for MYC inhibitors[J]. Science Advances, 2025, 11(29): eadw5228.