Northwestern Medicine investigators have discovered a new combination approach that may improve the efficacy of MYC inhibitor drugs for treating aggressive and treatment-resistant cancers, according to a recent Northwestern Medicine study published in Science Advances.
Sarki Abdulkadir, MD, PhD, the John T. Grayhack, MD, Professor of Urological Research and vice chair for research in the Department of Urology, was senior author of the study.
The MYC oncogene is an established driver of tumor growth and treatment resistance in more than half of all human cancers. While MYC has historically been difficult to therapeutically target, recently developed MYC inhibitors have shown promise in pre-clinical studies, including a small-molecule MYC inhibitor recently developed by Abdulkadir’s laboratory called MYCi975.
In the current study, Abdulkadir’s team conducted a genome-wide CRISPR screen in MYC-dependent prostate cancer cell lines treated with MYCi975 to identify potential targets that enhance the efficacy of MYC inhibitors.
“We had two questions. One was what kind of patients would respond most significantly to the treatment, that way you can preferentially give it to them and then you avoid giving it to those who may not benefit as much. The second question was what kind of drug can you combine with this new MYC treatment,” said Abdulkadir, who is also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
First, the scientists used CRISPR to systematically delete genes across the entire genome in prostate cancer cells. They then treated the cells with MYCi975 to determine which genes, when deleted, would increase the cells’ sensitivity to MYCi975.
“If you have a tumor in a patient that lacks the gene, then when you treat it with MYC inhibitor the tumor should respond better,” Abdulkadir said.
Unexpectedly, the investigators discovered in the cells one particular class of genes that was disrupted: mitochondrial complex I genes.
MYC helps cancer cells gain energy through enhancing the function of the mitochondrial process. The scientists found that when MYCi975 suppressed these genes, it reduced oxidative phosphorylation and glycolysis and triggered an upregulation in the mitochondrial complex I genes.
“The cells are now under pressure because there’s no energy and we found that the cells upregulate these complex I genes to try to compensate. At the same time, if you inhibit any one of these complex I genes, then the cells don’t like it because you are closing their options of getting energy,” Abdulkadir said.
The scientists also found that targeting these MYC-inhibited cells with the FDA-approved diabetes drug metformin, a mitochondrial complex I inhibitor, caused the cells to collapse due to metabolic stress.
“This strategy, which combines emerging MYC inhibitors with well-characterized metabolic drugs, provides an immediate translatable approach to improve treatment outcomes in patients with MYC-driven cancers,” the authors wrote.
The findings not only demonstrate a new therapeutic strategy for enhancing the efficacy of MYC inhibitors in treating MYC-driven cancers but also underscore the need to establish mitochondrial complex I genes as a biomarker, Abdulkadir said.
“If you can check tumors and those that have low levels of these complex I genes, then they should be more sensitive to not just our MYC inhibitor, but any MYC inhibitor developed in the future,” Abdulkadir said.
Abdulkadir is the co-leader of the of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University’s Prostate Cancer SPORE program. William Yang, a student in the Driskill Graduate Program in Life Sciences (DGP), was the lead author of the study.
Co-authors include James Parker, PhD, research associate professor of Obstetrics and Gynecology in the Division of Reproductive Science in Medicine; Adam Steffeck and Hao Pan, both DGP students; Debabrata Chakravarti, PhD, the Anna Lapham Professor of Obstetrics and Gynecology and the Vice Chair for Translational Research in the Department of Obstetrics and Gynecology; and Navdeep Chandel, PhD, the David W. Cugell, MD, Professor of Medicine in the Division of Pulmonary and Critical Care.
This work was supported by National Institutes of Health grants P50 CA180995 and R01 CA257258, the Prostate Cancer Foundation TACTICAL Award, and Polsky Urologic Cancer Institute.
