PTEN deficiency sensitizes endometrioid endometrial cancer to compound PARP-PI3K inhibition but not PARP inhibition as monotherapy

X Bian,J Gao,T Zheng,F Luo,Y Wang,H Cheng,J J Zhao,P Liu,D Wang,T M Roberts,C Rui

doi:10.1038/onc.2017.326

Abstract

Poly (ADP-ribose) polymerase (PARP) inhibitors have emerged as promising cancer therapeutics especially for tumors with deficient homologous recombination (HR) repair. However, as HR-deficient tumors represent only a small fraction of endometrial cancers, the therapeutic utility of PARP inhibitors is limited in this disease. Somatic loss of phosphatase and tensin homolog (PTEN), a tumor suppressor that counteracts phosphoinositide 3-kinase (PI3K) activity, is one of the most common genetic aberrations in endometrioid endometrial cancer. While previous works have identified the role of PTEN in DNA double-strand break repair, vulnerabilities of PTEN-deficient endometrioid endometrial cancers to PARP inhibition remain controversial. Here we find that PTEN-deficient endometrioid endometrial cancer cells are not responsive to PARP inhibitor Olaparib alone, but instead show superior sensitivity to compound inhibition with PI3K inhibitor BKM120, as evidenced by reduced clonogenic cell growth and three-dimensional (3D) spheroid disintegration. Mechanistically, PI3K blockade by BKM120 attenuated HR competency with γH2AX accumulation and reduced RAD51 and BRCA1 expression in Ishikawa, AN3CA and Nou-1 cells, but the same combination treatment led to enhanced phosphorylation of DNA-PK, a non-homologous end joining repair protein, in Hec-108 cells. Furthermore, we show that CRISPR/Cas9-mediated PTEN depletion rendered PTEN wild-type Hec-1A endometrioid endometrial cancer cells responsive to combined inhibition of PARP/PI3K, with concomitantly induced DNA damage accumulation and repair defects. The combination of BKM120 and Olaparib cooperated to inhibit tumor growth in a genetic mouse model of Pten-deficient endometrioid endometrial cancer. Together, these results suggest PI3K inhibition may be a plausible approach to expand the utility of PARP inhibitors to endometrioid endometrial cancers in a PTEN-deficient setting.

Highlights

Endometrial cancer is the most common gynecological malignancy among women in the developed country
To investigate how endometrioid endometrial cancer cells respond to poly (ADP-ribose) polymerase (PARP) inhibition, we treated several endometrioid endometrial cancer cell line models that lack phosphatase and tensin homolog (PTEN) (Ishikawa, AN3CA, Nou-1, and Hec-108) with PARP inhibitor Olaparib as single-agent or in combined with BKM120, a pan-class I phosphoinositide 3-kinase (PI3K) inhibitor
While previous studies have implicated the role of PTEN in homologous recombination (HR) repair, it remains controversial as to whether cancer cells with PTEN deficiency are vulnerable to PARP inhibitor treatment

Summary

Introduction

Endometrial cancer is the most common gynecological malignancy among women in the developed country It can be broadly classified into two types: majority (~80%) of endometrial cancers are of Type I endometrioid histology; up to 15% are of Type II, primarily serous carcinomas.[1,2] Most of endometrioid endometrial cancer patients present with low-grade and early-stage disease and have a favorable prognosis. A poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi), has been approved as the first ‘personalized therapy’ for advanced BRCA1/2 mutated ovarian cancer.[4] unlike ovarian cancers with nearly half of the cases bearing deficiency in homologous recombination (HR),[5] majority of endometrial cancers harbor intact HR pathway, which limits the therapeutic utility of PARP inhibitors in this disease. Olaparib and other PARP inhibitors as monotherapy or in combination therapies are being actively assessed in the treatment of a variety of cancer types bearing deficient BRCA, including ovarian cancer, prostate cancer and breast cancer.[6,7,8,9] recent studies reveal that the concept of synthetic lethality to target non-BRCA-mutant cancers with PARP inhibitors has clear potential.[10,11,12]

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Results

Conclusion