BKM120 sensitizes glioblastoma to the PARP inhibitor rucaparib by suppressing homologous recombination repair

Shaolu Zhang, Xin Peng, Xiaofei Li, Hongyan Liu, Baoquan Zhao, Moshe Elkabets, Yao Liu, Wei Wang, Ran Wang, Yuxu Zhong, Dexin Kong

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

PARP inhibitors have been approved for the therapy of cancers with homologous recombination (HR) deficiency based on the concept of “synthetic lethality”. However, glioblastoma (GBM) patients have gained little benefit from PARP inhibitors due to a lack of BRCA mutations. Herein, we demonstrated that concurrent treatment with the PARP inhibitor rucaparib and the PI3K inhibitor BKM120 showed synergetic anticancer effects on GBM U251 and U87MG cells. Mechanistically, BKM120 decreased expression of HR molecules, including RAD51 and BRCA1/2, and reduced HR repair efficiency in GBM cells, therefore increasing levels of apoptosis induced by rucaparib. Furthermore, we discovered that the two compounds complemented each other in DNA damage response and drug accumulation. Notably, in the zebrafish U87MG-RFP orthotopic xenograft model, nude mouse U87MG subcutaneous xenograft model and U87MG-Luc orthotopic xenograft model, combination showed obviously increased antitumor efficacy compared to each monotherapy. Immunohistochemical analysis of tumor tissues indicated that the combination obviously reduced expression of HR repair molecules and increased the DNA damage biomarker γ-H2AX, consistent with the in vitro results. Collectively, our findings provide new insight into combined blockade of PI3K and PARP, which might represent a promising therapeutic approach for GBM.

Original languageEnglish
Article number546
JournalCell Death and Disease
Volume12
Issue number6
DOIs
StatePublished - 1 Jun 2021

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