MCM2-7 complex is a novel druggable target for neuroendocrine prostate cancer

En-Chi Hsu,Manoj Kumar,Michelle Shen,Sharon J Pitteri,Fernando Garcia-Marques,Tanya Stoyanova,Merve Aslan,James D Brooks,Holly M Nguyen,Eva Corey,Shiqin Liu,Rosalie Nolley

doi:10.1038/s41598-021-92552-x

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.

Highlights

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
Four proteins of the MCM2 to MCM7 (MCM2-7) complex, including MCM2/3/4/6, were identified as highly elevated in the Trop2-driven neuroendocrine prostate cancer (TD-NEPC) model when compared to LNCaP prostate adenocarcinoma xenografts (Fig. 1A)
Elevated gene expression levels of MCM2/3/4/6 were observed in NCI-H660, a NEPC cell line, when compared to prostate adenocarcinoma cell lines and two castration resistant prostate cancer (CRPC) cell lines, 22Rv1 and DU145, showed slight up-regulation of MCM2/3/4/6 genes compared with LNCaP, VCaP, and PC-3 cell lines[17] (Fig. 1B)

Summary

Introduction

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. We demonstrate that MCM2/3/4/6 are significantly elevated in cell line and patient-derived xenograft (PDX) models of NEPC and, most importantly, in patient NEPC samples across three independent metastatic prostate cancer clinical datasets.

Methods

Results

Conclusion