researchers identified a protein that plays an important role in prostate cancer progression as well as resistance to enzalutamide, a common prostate cancer treatment.
Drugs targeting this protein 鈥 casein kinase 1 alpha (CK1伪) 鈥 could reverse enzalutamide resistance and improve outcomes for patients with prostate cancer, according to the study April 18.
Prostate cancer is the most common cancer and the second-leading cause of cancer mortality among men in the U.S., largely due to the development of therapy resistance during treatment.
Drugs like enzalutamide, which inhibit male hormones from activating the androgen receptor, have been a mainstay of care in the treatment of advanced prostate cancer. However, metastatic prostate cancers can develop resistance to enzalutamide and there is limited understanding about how this occurs.
鈥淥ur lab is the first to report the role of CK1伪 in prostate cancer progression and enzalutamide resistance,鈥 said Jinghui Liu, Ph.D., the study鈥檚 lead author and assistant professor in the 好色先生 College of Medicine鈥檚 Department of Toxicology and Cancer Biology.
鈥淲hat鈥檚 most exciting is that our findings have a very high potential to translate to clinical research and be immediately beneficial to patients with enzalutamide-resistant prostate cancer," said Liu, who is a researcher in the lab of Xiaoqi Liu, Ph.D., the chair of the department of Toxicology and Cancer Biology and Lucille P. Markey Endowed Chair in Oncology Research.
The study paves the way for the launch of a clinical trial utilizing a combination of a CK1伪 inhibitor called BTX-A51 with enzalutamide for treatment of late stage prostate cancer. BTX-A51 has already been approved by the Food and Drug Administration for its use in a clinical trial on acute myeloid leukemia.
Liu鈥檚 team used a CRISPR-Cas9 knockout screen to identify CK1伪 as a top therapeutic target. The study validates this finding using several preclinical models that show inhibiting CK1伪 greatly improves the effectiveness of enzalutamide.
The study also shines a light on how CK1伪 is linked to enzalutamide resistance. Using RNA sequencing and mass spectrometry analysis, the team found that CK1伪 modifies a protein called ataxia telangiectasia mutated (ATM). ATM initiates DNA damage response signaling, which is compromised in enzalutamide resistance.
With this understanding, ATM could also be utilized as a prognostic biomarker to predict the clinical outcome of enzalutamide.