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

Bian, Xiaoying; Gao, Jing; Luo, Fang; Rui, Chunhua; Zheng, Tingting; D, Wang; Wang, Y; Roberts, Thomas M.; Liu, P; Zhao, Jean J.; Cheng, Hai‐Ling Margaret

doi:10.1038/onc.2017.326

Cited by 91 publications

(85 citation statements)

References 48 publications

(73 reference statements)

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“…PTEN alterations are frequent in endometrial cancers, particularly in EEC and may modulate DSB-repair capacity by regulating the expression of RAD51 (20). In vitro studies have shown contradictory results, with some reporting no correlation between PTEN loss and HR deficiency (38,39), whereas others did find a correlation (40). In our study, we did not observe a correlation between HR capacity and IHC PTEN expression.…”

Section: Discussioncontrasting

confidence: 87%

Frequent Homologous Recombination Deficiency in High-grade Endometrial Carcinomas

Jonge

Auguste

Wijk

et al. 2019

Clinical Cancer Research

129

114

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Purpose: The elevated levels of somatic copy-number alterations (SCNAs) in a subset of high-risk endometrial cancers are suggestive of defects in pathways governing genome integrity. We sought to assess the prevalence of homologous recombination deficiency (HRD) in endometrial cancers and its association with histopathologic and molecular characteristics.Experimental Design: Fresh tumor tissue was prospectively collected from 36 endometrial cancers, and functional HRD was examined by the ability of replicating tumor cells to accumulate RAD51 protein at DNA double-strand breaks (RAD51 foci) induced by ionizing radiation. Genomic alterations were determined by next-generation sequencing and array comparative genomic hybridization/SNP array. The prevalence of BRCA-associated genomic scars, a surrogate marker for HRD, was determined in the The Cancer Genome Atlas (TCGA) endometrial cancer cohort.Results: Most endometrial cancers included in the final analysis (n ¼ 25) were of non-endometrioid (52%), grade 3 (60%) histology, and FIGO stage I (72%). HRD was observed in 24% (n ¼ 6) of cases and was restricted to non-endometrioid endometrial cancers (NEEC), with 46% of NEECs being HRD compared with none of the endometrioid endometrial cancers (EEC, P ¼ 0.014). All but 1 of the HRD cases harbored either a pathogenic BRCA1 variant or high somatic copy-number (SCN) losses of HR genes. Analysis of TCGA cases supported these results, with BRCA-associated genomic scars present in up to 48% (63/132) of NEEC versus 12% (37/312) of EEC (P < 0.001).Conclusions: HRD occurs in endometrial cancers and is largely restricted to non-endometrioid, TP53-mutant endometrial cancers. Evaluation of HRD may help select patients that could benefit from treatments targeting this defect, including platinum compounds and PARP inhibitors. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis):

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Section: Discussioncontrasting

confidence: 87%

Frequent Homologous Recombination Deficiency in High-grade Endometrial Carcinomas

Jonge

Auguste

Wijk

et al. 2019

Clinical Cancer Research

129

114

View full text Add to dashboard Cite

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“…Although PTEN mutation was previously reported as a marker to predict sensitivity to PARP inhibitors, more recent evidence shows that PTEN mutation will cause an activation of the PI3K pathway. Hence, PTEN ‐mutated tumors would not respond to monotherapy of PARP inhibitors . Neither are PTEN ‐mutated tumors sensitive to platinum‐based treatment in chemotherapy .…”

Section: Discussionmentioning

confidence: 99%

Using next‐generation sequencing to redefineBRCAnessin triple‐negative breast cancer

et al. 2020

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This is an open access article under the terms of the Creat ive Commo ns Attri bution-NonCo mmercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. AbstractBRCAness is considered a predictive biomarker to platinum and poly(ADP-ribose) polymerase (PARP) inhibitors. However, recent trials showed that its predictive value was limited in triple-negative breast cancer (TNBC) treated with platinum. Moreover, tumors with mutations of DNA damage response (DDR) genes, such as homologous recombination (HR) genes, could be sensitive to platinum and PARP inhibitors. Thus, we aim to explore the relationship between mutation status of DDR genes and BRCAness in TNBC. We sequenced 56 DDR genes in 120 TNBC and identified BRCAness by array comparative genomic hybridization. The sequencing results showed that 13, 14, and 14 patients had BRCA, non-BRCA HR, and non-HR DDR gene mutations, respectively.Array comparative genomic hybridization revealed that BRCA-mutated and HR genemutated TNBC shared similar BRCAness features, both having higher numbers and longer length of large-scale structural aberration (LSA, >10 Mb) and similar altered chromosomal regions of LSA. These suggested non-BRCA HR gene-mutated TNBC shared similar characteristics with BRCA-mutated TNBC, indicating non-BRCA HR gene-mutated TNBC sensitive to platinum and PARP inhibitors. Among tumors with mutation of non-HR DDR genes, 3 PTEN and 1 MSH6 mutation also contained significant LSAs (BRCAness); however, they had different regions of genomic alteration to BRCA and HR gene-mutated tumors, might explain prior findings that PTEN-and MSH6-mutated cancer cells not sensitive to PARP inhibitors. Therefore, we hypothesize that the heterogeneous genomic background of BRCAness indicates different responsiveness to platinum and PARP inhibitors. Direct sequencing DDR genes in TNBC should be applied to predict their sensitivity toward platinum and PARP inhibitors.

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“…PTEN-deficient tumor cells display a defect in HR due to defective expression and chromatin loading of RAD51 (12,16,43) and hence could be targeted by PARP inhibitors (30,43,44). In fact, PTEN deficiency sensitizes endometroid endometrial cancer to PARP inhibition alone (45) or in combination with PI3K pathway inhibition (46). In the present study, we confirmed these previous reports, but importantly, we found that Ishikawa EndoCA cells lacking nuclear PTEN are more sensitive to Olaparib, whereas cells with nuclear PTEN show an attenuated affect.…”

Section: Discussionmentioning

confidence: 99%

Nuclear PTEN Localization Contributes to DNA Damage Response in Endometrial Adenocarcinoma and Could Have a Diagnostic Benefit for Therapeutic Management of the Disease

Mukherjee

Patterson

George

et al. 2018

Molecular Cancer Therapeutics

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Endometrial adenocarcinoma (EndoCA) is the most common gynecologic cancer type in the United States, and its incidence is increasing. The majority of patients are disease-free after surgical resection of stage I tumors, which is often followed by radiotherapy, but most patients with advanced disease recur and have a poor prognosis, largely because the tumors become refractory to cytotoxic chemotherapies. PTEN, a commonly mutated tumor suppressor in EndoCAs, is well known for its ability to inhibit the AKT/mTOR signaling pathway. Nuclear functions for PTEN have been proposed as well, but whether those affect EndoCA development, progression, or outcomes is not well understood. Using immunohistochemistry, nuclear PTEN expression was observed in approximately half of EndoCA patient tumors, independent of grade and cytoplasmic PTEN expression. Higher levels of the DNA damage response (DDR) marker, γH2AX, were observed by immunohistochemistry and immunofluorescence in human EndoCA tumor sections that were PTEN-negative, in murine EndoCA tissues that were genetically modified to be PTEN-null, and in Ishikawa EndoCA cells, which do not express endogenous PTEN. Overexpression of exogenous PTEN-WT or PTEN-NLS, a modified PTEN with an added nuclear localization signal, significantly improved both DDR and G-M transition in Ishikawa cells treated with a DNA-damaging agent. Whereas PARP inhibition with Olaparib was not as effective in Ishikawa cells expressing native or PTEN-NLS, inhibition with Talazoparib was not affected by PTEN overexpression. These results suggest that nuclear PTEN subcellular localization in human EndoCA could be diagnostic when considering DDR therapeutic intervention. .

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

Cited by 91 publications

References 48 publications

Frequent Homologous Recombination Deficiency in High-grade Endometrial Carcinomas

Frequent Homologous Recombination Deficiency in High-grade Endometrial Carcinomas

Using next‐generation sequencing to redefineBRCAnessin triple‐negative breast cancer

Nuclear PTEN Localization Contributes to DNA Damage Response in Endometrial Adenocarcinoma and Could Have a Diagnostic Benefit for Therapeutic Management of the Disease

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