IGFBP3 promotes resistance to Olaparib via modulating EGFR signaling in advanced prostate cancer
Amy R. Leslie,
Shu Ning,
Cameron M. Armstrong,
Leandro S. D’Abronzo,
Masuda Sharifi,
Zachary A. Schaaf,
Wei Lou,
Chengfei Liu,
Christopher P. Evans,
Alan P. Lombard,
Allen C. Gao
Affiliations
Amy R. Leslie
Department of Urologic Surgery, University of California Davis, Davis, CA, USA
Shu Ning
Department of Urologic Surgery, University of California Davis, Davis, CA, USA
Cameron M. Armstrong
Department of Urologic Surgery, University of California Davis, Davis, CA, USA
Leandro S. D’Abronzo
Department of Urologic Surgery, University of California Davis, Davis, CA, USA
Masuda Sharifi
Department of Urologic Surgery, University of California Davis, Davis, CA, USA
Zachary A. Schaaf
Department of Urologic Surgery, University of California Davis, Davis, CA, USA
Wei Lou
Department of Urologic Surgery, University of California Davis, Davis, CA, USA
Chengfei Liu
Department of Urologic Surgery, University of California Davis, Davis, CA, USA; UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA, USA
Christopher P. Evans
Department of Urologic Surgery, University of California Davis, Davis, CA, USA; UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA, USA
Alan P. Lombard
Department of Urologic Surgery, University of California Davis, Davis, CA, USA; Department of Biochemistry and Molecular Medicine, University of California Davis, Davis, CA, USA
Allen C. Gao
Department of Urologic Surgery, University of California Davis, Davis, CA, USA; UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA, USA; VA Northern California Health Care System, Sacramento, CA, USA; Corresponding author
Summary: Olaparib is a pioneering PARP inhibitor (PARPi) approved for treating castration-resistant prostate cancer (CRPC) tumors harboring DNA repair defects, but clinical resistance has been documented. To study acquired resistance, we developed Olaparib-resistant (OlapR) cell lines through chronic Olaparib treatment of LNCaP and C4-2B cell lines. Here, we found that IGFBP3 is highly expressed in acquired (OlapR) and intrinsic (Rv1) models of Olaparib resistance. We show that IGFBP3 expression promotes Olaparib resistance by enhancing DNA repair capacity through activation of EGFR and DNA-PKcs. IGFBP3 depletion enhances efficacy of Olaparib by promoting DNA damage accumulation and subsequently, cell death in resistant models. Mechanistically, we show that silencing IGFBP3 or EGFR expression reduces cell viability and resensitizes OlapR cells to Olaparib treatment. Inhibition of EGFR by Gefitinib suppressed growth of OlapR cells and improved Olaparib sensitivity, thereby phenocopying IGFBP3 inhibition. Collectively, our results highlight IGFBP3 and EGFR as critical mediators of Olaparib resistance.
