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Ref Type Journal Article
PMID (28945226)
Authors Bian X, Gao J, Luo F, Rui C, Zheng T, Wang D, Wang Y, Roberts TM, Liu P, Zhao JJ, Cheng H
Title PTEN deficiency sensitizes endometrioid endometrial cancer to compound PARP-PI3K inhibition but not PARP inhibition as monotherapy.
Journal Oncogene
Vol 37
Issue 3
Date 2018 01 18
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PTEN del endometrial carcinoma sensitive Buparlisib Preclinical - Cell culture Actionable In a preclinical study, Buparlisib (BKM120) inhibited Akt signaling, induced DNA damage, and inhibited the growth of an endometrial carcinoma cell line with PTEN knocked out via CRISPR/Cas9 system in culture (PMID: 28945226). 28945226
PTEN del endometrial carcinoma sensitive Buparlisib + Olaparib Preclinical - Cell culture Actionable In a preclinical study, the combination of Buparlisib (BKM120) and Lynparza (olaparib) resulted in enhanced DNA damage and growth inhibition in an endometrial carcinoma cell line with PTEN knocked out via CRISPR/Cas9 system in culture (PMID: 28945226). 28945226
PTEN del STK11 del endometrial carcinoma no benefit Olaparib Preclinical Actionable In a preclinical study, Lynparza (olaparib) monotherapy demonstrated limited anti-tumor effect in a STK11 and PTEN double knock-out mouse model of endometrial carcinoma (PMID: 28945226). 28945226
PTEN del STK11 del endometrial carcinoma sensitive Buparlisib + Olaparib Preclinical Actionable In a preclinical study, the combination of Buparlisib (BKM120) and Lynparza (olaparib) significantly induced apoptosis and reduced tumor volume by 1.83 fold in a STK11 and PTEN double knock-out mouse model of endometrial carcinoma (PMID: 28945226). 28945226
PTEN negative endometrial carcinoma no benefit Olaparib Preclinical - Cell culture Actionable In a preclinical study, Lynparza (olaparib) treatment did not significantly increase DNA damage or inhibit growth of PTEN-deficient endometrial carcinoma cell lines in culture (PMID: 28945226). 28945226
PTEN del STK11 del endometrial carcinoma predicted - sensitive Buparlisib Preclinical Actionable In a preclinical study, Buparlisib (BKM120) monotherapy resulted in stable disease in a STK11 and PTEN double knock-out mouse model of endometrial carcinoma (PMID: 28945226). 28945226
PTEN negative endometrial carcinoma sensitive Buparlisib + Olaparib Preclinical - Cell culture Actionable In a preclinical study, the combination of Buparlisib (BKM120) and Lynparza (olaparib) resulted in enhanced DNA damage and growth inhibition in PTEN-deficient endometrial carcinoma cell lines in culture (PMID: 28945226). 28945226
PTEN del endometrial carcinoma no benefit Olaparib Preclinical - Cell culture Actionable In a preclinical study, Lynparza (olaparib) treatment did not significantly increase DNA damage or inhibit growth of an endometrial carcinoma cell line with PTEN knocked out via CRISPR/Cas9 system in culture (PMID: 28945226). 28945226
PTEN negative endometrial carcinoma sensitive Buparlisib Preclinical - Cell culture Actionable In a preclinical study, Buparlisib (BKM120) inhibited Akt signaling, induced DNA damage, and inhibited the growth of PTEN-deficient endometrial carcinoma cell lines in culture (PMID: 28945226). 28945226