CDK12 Loss a Biomarker for Prostate Cancer Response to Immunotherapy?

DNA and RNA sequencing results suggest prostate cancer treatment “involving inhibition of CDK12 and immune checkpoint blockade,” a U Michigan team said.

Analyzing DNA and RNA sequencing data from 360 metastatic castration-resistant prostate cancer (mCRPC) samples, researchers have discovered a gene mutation that could possibly help identify which patients will benefit from immune checkpoint inhibition therapy, they reported in Cell.

Biallelic CDK12 gene-deletion mutations, in which both copies of CDK12 are lost from the tumor genome, were more frequent in mCRPC than early-stage, localized prostate tumor samples (7% vs 1%), the authors found.

“Because prostate cancer is so common, 7 percent is a significant number,” noted senior study author Arul Chinnaiyan, MD, PhD, director of the Michigan Center for Translational Pathology at the University of Michigan in Ann Arbor, in a press release.

Tumors with CDK12 loss exhibited higher levels of genomic instability, gene-fusion mutations, and resulting cell-surface neoantigens that might be recognized as foreign to patients’ immune cells, Chinnaiyan’s team reported.

Tumor samples with biallelic CDK12 loss also had higher levels of immune T-cell infiltration and T-cell clonal expansion, bolstering the case for these tumors’ immunogenicity.

Men with prostate cancer have seen limited benefits from immune checkpoint blockade compared to patients with some other cancer types. Researchers have been searching for predictive molecular biomarkers with which to identify patients who are likely to benefit from immunotherapy.

“This very promising study suggests that CDK12 loss may be a biomarker for identifying prostate cancer patients who may respond to checkpoint immunotherapy,” said Howard Soule, PhD, of the Prostate Cancer Foundation in Santa Monica, California.

The research team conducted a very small pilot study of four patients and found that two of the men experienced “exceptional” declines in prostate-specific antigen (PSA) levels when treated with pembrolizumab, an immune checkpoint inhibitor that targets programmed death 1 (PD-1).

“Furthermore, identification of CDK12 mutation–associated neoantigens may help in the design of personalized tumor vaccines,” the team noted. “The immune phenotype of CDK12-mutated tumors may also broadly suggest a combinational strategy for prostate cancer treatment involving inhibition of CDK12 and immune checkpoint blockade.”

CDK12 aberrations have also been tied to ovarian cancer, the researchers noted.

The study was funded by the Prostate Cancer Foundation, the US National Cancer Institute, Howard Hughes Medical Institute, the American Cancer Society, and the US Department of Defense.