In a study published July 7 in npj Precision Oncology, University of Michigan researchers at the Department of Internal Medicine and Rogel Cancer Center identified a gene program, or specific set of genes, associated with extreme non-response to a common prostate cancer drug, enzalutamide. The research, led by Joshi Alumkal, U-M internal medicine professor, and Zheng Xia, computational biology professor at Oregon Health & Science University provides a potential explanation for why some tumors are treatment-resistant and explores potential new treatment strategies for patients with aggressive tumors.
In an email to The Michigan Daily, Alumkal wrote he was inspired by his clinical experience to investigate treatment resistance.
“I take care of patients with prostate cancer in the clinic,” Alumkal wrote. “The patients whose tumors grow right through drugs like enzalutamide have the worst clinical outcomes. Thus, we were motivated to find out why these tumors are so aggressive and identify possible treatment strategies that might work better in these patients.”
Alumkal wrote a gene program identified in the study was linked to extreme non-response, characterized by aggressive tumor behavior and resistance to treatment.
“This program is enriched for genes important for cell growth and primitiveness,” Alumkal wrote. “These genes appeared to be highly related to poor treatment outcomes in the initial group of patients we examined in addition to patient samples from several other studies. In summary, it may help explain why certain tumors behave very aggressively despite treatments like enzalutamide. Such a gene program was not well-described previously.”
In an email to The Daily, LSA rising senior Ali Haidar, founder and president of Remission Detroit, wrote that identifying therapies other than enzalutamide can help remedy treatment-resistant tumors.
“Something that really stood out to me about the study’s identification of the ENR gene program is that even though these tumors didn’t respond to one type of treatment, they could respond to others,” Haidar wrote. “To me, this is a strong reminder that even if a tumor is resistant to one therapy, it doesn’t necessarily mean that it’s untreatable.”
Alumkal wrote the study specifically focused on CDK2, a protein kinase associated with cancer initiation and progression, as a potential source of treatment resistance because drugs already exist to block it.
“CDK2 was one of the top activated kinases in our analysis,” Alumkal wrote. “Importantly, there are now drugs to block CDK2. Because our goal was to identify genes that might be targeted, we zeroed in on CDK2.”
Rackham student Yihan Liu wrote in an email to The Daily that, because CDK2 is active in the cell replication process, inhibiting it may directly reduce the growth and spread of prostate cancer.
“In ENR program-high prostate cancer, CDK2 was shown to drive aggressive gene programs; inhibiting CDK2 decreased both expression of these programs and cell survival,” Liu wrote. “Because CDK2 is directly tied to cell cycle progression, and its inhibition disrupts proliferation and characteristics linked to metastasis, I think it offers a targeted strategy for controlling both growth and spread, particularly with so many CDK2 selective inhibitors in early clinical trials.”
In an email to The Daily, Medical School student Amina Tanweer wrote molecular research such as the researchers’ study intersects with epidemiologic research to enhance understanding of cancer disparities and guide future clinical applications.
“Research on enzalutamide resistance, particularly studies that uncover molecular mechanisms such as the ENR gene program, provides critical insight into the biological underpinnings of treatment failure,” Tanweer wrote. “This mechanistic understanding complements population-level cancer studies by offering specific targets and hypotheses that can be explored epidemiologically. While population-level studies identify patterns, disparities, and risk factors across diverse groups, mechanistic studies explain why those patterns might exist at the cellular level.”
Haidar wrote support from community organizations, such as Remission Detroit, is important to ensure all patients can access treatment found to be effective in research.
“At the end of the day, all cancer research is good research,” Haidar wrote. “Every discovery helps us better understand these diseases and how to fight them. At the same time, we need to make sure that the benefits of those discoveries reach everyone, not just those with the best insurance or the most resources. That’s where advocacy, community support, and patient-centered organizations come in. That’s where organizations like Remission Detroit can play a role. We can help raise awareness, advocate for insurance coverage, and support the scientists and physicians conducting this research.”
Daily Staff Reporter Kayla Lugo can be reached at klugo@umich.edu.
