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

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

doi:10.1038/s41419-021-03805-6

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.

Highlights

Glioblastoma (GBM), the most malignant tumor of the adult central nervous system, represents up to 50% of all primary brain gliomas[1]
Poly (ADP-ribose) polymerase (PARP) inhibition causes double-strand break (DSB) accumulation during DNA replication and induces apoptosis, in cells with homologous recombination (HR) deficiency. This is the basis for the synthetic lethality of PARP inhibitors (PARPis) in cancers with HR deficiency due to mutations in BRCA1/2 or other HR genes[5], allowing these cancer cells to be selectively targeted while sparing normal cells that have intact DNA repair systems[6]
In most cases, BRCA1/2 can be recruited to damaged DNA for the repair of DSBs, reducing the antitumor efficiency of PARPis[17]

Summary

Introduction

Glioblastoma (GBM), the most malignant tumor of the adult central nervous system, represents up to 50% of all primary brain gliomas[1]. Current GBM therapy, including aggressive surgical resection, high-dose external beam radiation therapy (RT), and temozolomide (TMZ) chemotherapy, is only associated with a median time to progression of 6 months and a median overall survival of. PARP inhibition causes double-strand break (DSB) accumulation during DNA replication and induces apoptosis, in cells with homologous recombination (HR) deficiency. This is the basis for the synthetic lethality of PARP inhibitors (PARPis) in cancers with HR deficiency due to mutations in BRCA1/2 or other HR genes[5], allowing these cancer cells to be selectively targeted while sparing normal cells that have intact DNA repair systems[6]. Most recently, targeting autophagy was demonstrated to enhance the therapeutic efficacy of Official journal of the Cell Death Differentiation Association

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Conclusion