MCM2-7 complex is a novel druggable target for neuroendocrine prostate cancer. Scientific reports Hsu, E. C., Shen, M., Aslan, M., Liu, S., Kumar, M., Garcia-Marques, F., Nguyen, H. M., Nolley, R., Pitteri, S. J., Corey, E., Brooks, J. D., Stoyanova, T. 2021; 11 (1): 13305

Abstract

Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer that rarely develops de novo in primary tumors and is commonly acquired during the development of treatment resistance. NEPC is characterized by gain of neuroendocrine markers and loss of androgen receptor (AR), making it resistant to current therapeutic strategies targeting the AR signaling axis. Here, we report that MCM2, MCM3, MCM4, and MCM6 (MCM2/3/4/6) are elevated in human NEPC and high levels of MCM2/3/4/6 are associated with liver metastasis and poor survival in prostate cancer patients. MCM2/3/4/6 are four out of six proteins that form a core DNA helicase (MCM2-7) responsible for unwinding DNA forks during DNA replication. Inhibition of MCM2-7 by treatment with ciprofloxacin inhibits NEPC cell proliferation and migration in vitro, significantly delays NEPC tumor xenograft growth, and partially reverses the neuroendocrine phenotype in vivo. Our study reveals the clinical relevance of MCM2/3/4/6 proteins in NEPC and suggests that inhibition of MCM2-7 may represent a new therapeutic strategy for NEPC.

View details for DOI 10.1038/s41598-021-92552-x

View details for PubMedID 34172788