Investigators at UT Southwestern Medical Center have published research this week in the journal Cancer Cell that shows the loss of a gene in prostate tumors drives resistance to targeted therapies. The gene, known as SYNCRIP, unleashes cellular machinery that creates random mutations throughout the genome that drives the therapy resistance, and its discovery provides a pathway for the development of new interventions that can thwart this activity not only in prostate cancer, but other cancers as well.
“This study paves the way for innovative strategies to fix the broken ‘brake’ for mutagenesis in cancer and curb resistance to treatments,” said study leader Ping Mu, PhD, assistant professor of Molecular Biology at UT Southwestern.
While it is known that specific mutations within DNA play a role in the initiation of cancer and that other mutations that help cause cancer to grow and spread are common, targeted therapies for cancer have addressed specific targets but aren’t able to address the range of mutations present. The more mutations present, the more resistant a tumor is to treatment, but how the additional mutations occur so quickly has not been known.
The UT Southwestern team sought to find some of these answers. The Mu lab specializes in prostate cancer research, so the lab’s team looked for genetic differences in cells of prostate tumor from samples collected from xenografted human tumors before and after patients were given antiandrogen therapy. Antiandrogen therapy is often used to treat prostate cancer as it starves tumors of the sex hormones prostate cancer uses to grow. This form of treatment is typically effective for a time, but in most instances prostate cancer tumors eventually become resistant to this form of treatment.
In their examination, the investigators discovered that in about half of the post-treatment samples the SYNCRIP gene was missing. In addition, they found that a variety of mutations bore the signature of APOBEC proteins which produce a specific type of mutation used for immune defense in healthy cells.
Further researcher into the role of SYNCRIP showed that it serves as a “brake” for a major member of the APOBEC protein family, APOBEC3B, regulating its activity. But when SYNCRIP is lost, APOBEC3B’s function is not regulated, and this lack of control leads it to create random mutations throughout the genome. When the researchers altered the cells to remove APOBEC3B, the cells didn’t accumulate mutations proving its activity is linked to the SYNCRIP gene.
Tumor mutational burden and heterogeneity has been suggested to fuel resistance to many targeted therapies,” the researchers write in their findings. “The cytosine deaminase APOBEC proteins have been implicated in the mutational signatures of more than 70% of human cancers. However, the mechanism underlying how cancer cells hijack the APOBEC mediated mutagenesis machinery to promote tumor heterogeneity, and thereby foster therapy resistance remains unclear. We identify SYNCRIP as an endogenous molecular brake which suppresses APOBEC-driven mutagenesis in prostate cancer.”
Using this information as a basis, the researchers then looked for specific genetic drivers of tumor growth that arise from this activity and identified eight genes that appear to be hot spots for APOBEC-driven mutations. All eight made antiandrogen therapy ineffective and when they were deleted from the cells, they once again became responsive to that therapy.
These results suggest a potential new route to make therapy for prostate cancer more effective by eliminating the factors that drive antiandrogen therapy resistance.
“Despite the clinical success of AR-targeted therapies in managing (prostate cancer), the rapid emergence of resistance significantly limits patient outcomes. Our findings underscore the critical role of SYNCRIP and APOBEC3B-driven mutagenesis in facilitating therapy resistance. Our results propose targeting aberrant APOBEC3B activity as a potential therapeutic strategy to prevent or slow down resistance. Importantly, our results indicate that the administration of the APOBEC3B inhibitor would be more likely to slow down APOBEC-driven AR therapy resistance if given earlier,” the researchers conclude.
