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Silencing of BRCA2 to Identify Novel BRCA2-regulated Biological Functions in Cultured Human Cells

Silencing of BRCA2 to Identify Novel BRCA2-regulated Biological Functions in Cultured Human Cells

Published on: August 12, 2015

Targeting FGFR1 enhances olaparib sensitivity via MAPK-mediated BRCA2 downregulation in mCRPC

Jian Chen¹, Jiarun Lai¹, Yupeng Chen²

¹Guangdong Provincial Key Laboratory of Urology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.

Translational Andrology and Urology

|November 13, 2025

Abstract

Background:

Olaparib has demonstrated therapeutic potential in treating metastatic castration-resistant prostate cancer (mCRPC) harboring homologous recombination repair (HRR) gene mutations, especially BRCA2. However, resistance to PARP inhibition remains a significant clinical hurdle. Recent evidence suggests frequent activation of fibroblast growth factor receptor 1 (FGFR1) signaling in mCRPC, yet its impact on DNA repair regulation is poorly understood. This study aimed to investigate whether FGFR1 signaling modulates BRCA2 expression and contributes to PARP inhibitor resistance.

Methods:

We performed integrative transcriptomic analyses of multiple mCRPC datasets to examine the correlation between FGFR1 and BRCA2 expression. Functional assays including genetic knockdown, pharmacological inhibition, and overexpression studies were conducted in DU145 and PC3 cells. In vitro and in vivo models were employed to evaluate the impact of FGFR1 modulation on olaparib sensitivity, apoptosis, and proliferation. Gene set enrichment analysis (GSEA) was used to identify FGFR1-associated pathways. Western blotting and pathway inhibition experiments were used to dissect the underlying mechanism.

Results:

In this study, integrative transcriptomic analyses of multiple mCRPC datasets revealed a strong positive correlation between FGFR1 and BRCA2 expression. Functional assays in DU145 cells, which exhibit high FGFR1 and BRCA2 levels, demonstrated that genetic knockdown or pharmacological inhibition of FGFR1 (via PD173074) markedly reduced BRCA2 expression. FGFR1 inhibition significantly enhanced olaparib sensitivity by promoting apoptosis and suppressing cell proliferation both in vitro and in vivo. Gene set enrichment analyses stratified by BRCA2 levels converged on MAPK as the predominant FGFR1-downstream pathway linked to BRCA2. Mechanistically, FGFR1 functions as an upstream regulator of BRCA2, contributing to sustained HRR activity and attenuated response to PARP inhibition. Complementarily, transient FGFR1 overexpression in PC3 elevated phosphorylated-ERK and BRCA2, whereas MAPK inhibition blunted phosphorylated-ERK and attenuated BRCA2 induction, supporting an FGFR1-MAPK/ERK-BRCA2 axis.

Conclusions:

Together, these data reveal an FGFR1-driven, MAPK-dependent mechanism that sustains BRCA2 and attenuates PARP-inhibitor activity, nominate FGFR1 status as a candidate biomarker of PARP-inhibitor responsiveness, and support biomarker-guided co-targeting of FGFR1 and PARP in BRCA2-dependent mCRPC.

Insights

Fibroblast growth factor receptor 1 (FGFR1) signaling sustains BRCA2 expression, leading to resistance against PARP inhibitors like olaparib in metastatic castration-resistant prostate cancer (mCRPC). Inhibiting FGFR1 restores sensitivity to PARP inhibitors.

Area of Science:

Oncology
Molecular Biology
Genetics

Background:

Olaparib shows promise for metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair (HRR) gene mutations, particularly BRCA2.
Resistance to PARP inhibitors is a clinical challenge.
Fibroblast growth factor receptor 1 (FGFR1) signaling is often activated in mCRPC, but its role in DNA repair regulation is unclear.

Purpose of the Study:

To investigate if FGFR1 signaling influences BRCA2 expression.
To determine if FGFR1 signaling contributes to resistance against PARP inhibitors.

Main Methods:

Integrative transcriptomic analyses of mCRPC datasets to correlate FGFR1 and BRCA2 expression.
Functional assays (knockdown, inhibition, overexpression) in prostate cancer cell lines (DU145, PC3).
In vitro and in vivo models to assess FGFR1 modulation effects on olaparib sensitivity, apoptosis, and proliferation.
Gene set enrichment analysis (GSEA) to identify FGFR1-associated pathways.
Western blotting and pathway inhibition experiments to elucidate the mechanism.

Main Results:

A strong positive correlation was found between FGFR1 and BRCA2 expression in mCRPC datasets.
FGFR1 inhibition (genetic or pharmacological) significantly reduced BRCA2 expression and enhanced olaparib sensitivity in vitro and in vivo.
The MAPK/ERK pathway was identified as the predominant FGFR1-downstream pathway linked to BRCA2, forming an FGFR1-MAPK/ERK-BRCA2 axis.

Conclusions:

FGFR1 signaling drives a MAPK-dependent mechanism that maintains BRCA2 expression, leading to resistance to PARP inhibitors.
FGFR1 status may serve as a predictive biomarker for PARP inhibitor response in mCRPC.
Targeting FGFR1 in combination with PARP inhibitors could be a viable strategy for BRCA2-dependent mCRPC.

Read full analysis

Keywords:

BRCA2 Olaparib PARP inhibitor resistance fibroblast growth factor receptor 1 (FGFR1)metastatic castration-resistant prostate cancer (mCRPC)

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