A newly discovered inhibitor of a common cancer-causing protein acts selectively to reduce the expression of genes that promote cell proliferation and alter the epigenome, according to a Northwestern Medicine study published in the journal Science Advances.
According to Debabrata Chakravarty, Ph.D., Anna Lapham, professor of obstetrics and gynecology, vice chair of translational research in the Department of Obstetrics and Gynecology and co-author of the study, this protein, called MYC, was previously thought to be “not treatable,” but these new results show that certain inhibitors can selectively affect pro-cancerous processes.
“These results form the basis for the development and testing of all new lines of compounds for inhibiting MYC,” said Chakravarty, who is also a professor of pharmacology and assistant director of general resources at Northwestern University’s Robert H. Lurie Comprehensive Cancer Center.
MYC is a transcription factor protein that normally upregulates genes involved in cell proliferation. This transcription factor is consistently overexpressed in many cancers, however the development of inhibitors is hampered both by the protein’s unusual structure and its significant influence outside of cell proliferation, meaning that previous inhibitors have had severe toxic side effects.
In the current study, scientists introduced a small molecule inhibitor MYCi975 into prostate cancer cells and studied its effect on gene expression throughout the human genome. Surprisingly, the MYCi inhibitor does not have a broad downregulation of all MYC targets, but a variable effect, upregulating some genes, downregulating others, and completely eliminating some.
“So we were able to get information about drug selectivity,” says Austin Holmes, a recent graduate of the Driskill Graduate Program in Life Sciences (DGP) and lead author of the study.
Importantly, some genes that are essential for cell functionality and that may have been responsible for the toxicity of previous MYC inhibitors remained intact, according to Sarki Abdulkadir, M.D., Ph.D. urology and co-author of the study.
“Not all MYC functions have been abolished,” said Abdulkadir, who is also a professor of pathology and principal investigator for the Specialized Program for Advanced Research (SPORE) in prostate cancer at Luri Cancer Center. “This gives us a certain selectivity that has not been demonstrated before”
On the other hand, several cancer-associated MYC targets were reduced, which maintained the anti-cancer effect of the inhibitor. The realization that MYC inhibitors can have different effects on downstream MYC target genes opens up a new avenue for drug development, Chakravarty says.
“Excitingly, in animal models, MYCi975 enhances the efficacy of enzalutamide antihormonal therapy. We hope to use this platform to analyze second- or third-generation compounds and explore how these drugs might interact with existing cancer therapies,” Chakravarty said. “This study is also a prototype of how collaborative research can lead to significant discoveries in biomedical research”