MCM2-7 complex is a novel druggable target for neuroendocrine prostate cancer
En-Chi Hsu1,2, Michelle Shen1,2, Merve Aslan1,2
1Department of Radiology, Stanford University, 3155 Porter Drive, Palo Alto, CA, 94304, USA.
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.
Insights
Neuroendocrine prostate cancer (NEPC) shows elevated MCM2/3/4/6 proteins, linked to metastasis and poor survival. Inhibiting the MCM2-7 DNA helicase may offer a new therapeutic strategy for NEPC.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Neuroendocrine prostate cancer (NEPC) is a treatment-resistant subtype of prostate cancer.
- NEPC is characterized by neuroendocrine marker expression and loss of androgen receptor (AR) signaling.
- Current therapies targeting AR are ineffective against NEPC.
Purpose of the Study:
- To investigate the role of MCM2, MCM3, MCM4, and MCM6 (MCM2/3/4/6) proteins in NEPC.
- To explore the therapeutic potential of inhibiting the MCM2-7 DNA helicase in NEPC.
Main Methods:
- Quantification of MCM2/3/4/6 protein levels in human NEPC samples.
- Assessment of MCM2/3/4/6 levels' association with clinical outcomes like liver metastasis and patient survival.
- In vitro and in vivo experiments using ciprofloxacin to inhibit MCM2-7 function in NEPC models.
Main Results:
- Elevated MCM2/3/4/6 levels were observed in human NEPC.
- High MCM2/3/4/6 expression correlated with liver metastasis and reduced survival in prostate cancer patients.
- Ciprofloxacin treatment inhibited NEPC cell proliferation and migration, delayed tumor growth in vivo, and partially reversed the neuroendocrine phenotype.
Conclusions:
- MCM2/3/4/6 proteins have clinical relevance in NEPC.
- Inhibition of the MCM2-7 DNA helicase presents a promising novel therapeutic strategy for NEPC.
