FDI-6 Inhibits the Expression and Function of FOXM1 to Sensitize BRCA-proficient Triple-negative Breast Cancer Cells to Olaparib by Regulating Cell Cycle Progression and DNA Damage Repair

Overview

Journal Cell Death Dis

Specialties Cell Biology
General Medicine

Date 2021 Dec 9

PMID 34880209

Citations 14

Authors

Shu-Ping Wang

Shi-Qi Wu

Shi-Hui Huang

Yi-Xuan Tang

Liu-Qiong Meng

Feng Liu

Qi-Hua Zhu

Yun-Gen Xu

Affiliations

Soon will be listed here.

Abstract

Inducing homologous-recombination (HR) deficiency is an effective strategy to broaden the indications of PARP inhibitors in the treatment of triple-negative breast cancer (TNBC). Herein, we find that repression of the oncogenic transcription factor FOXM1 using FOXM1 shRNA or FOXM1 inhibitor FDI-6 can sensitize BRCA-proficient TNBC to PARP inhibitor Olaparib in vitro and in vivo. Mechanistic studies show that Olaparib causes adaptive resistance by arresting the cell cycle at S and G/M phases for HR repair, increasing the expression of CDK6, CCND1, CDK1, CCNA1, CCNB1, and CDC25B to promote cell cycle progression, and inducing the overexpression of FOXM1, PARP1/2, BRCA1/2, and Rad51 to activate precise repair of damaged DNA. FDI-6 inhibits the expression of FOXM1, PARP1/2, and genes involved in cell cycle control and DNA damage repair to sensitize TNBC cells to Olaparib by blocking cell cycle progression and DNA damage repair. Simultaneously targeting FOXM1 and PARP1/2 is an innovative therapy for more patients with TNBC.

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