EZH2 Loss Drives Resistance to Carboplatin and Paclitaxel in Serous Ovarian Cancers Expressing ATM

Naskou, Johanna; Beiter, Yvonne; Rensburg, Ruan van; Honisch, Ellen; Rudelius, Martina; Schlensog, Martin; Gottstein, Julia; Walter, Larissa; Braicu, Elena Ioana; Sehouli, Jalid; Darb‐Esfahani, Silvia; Staebler, Annette; Hartkopf, Andreas; Brucker, Sara; Wallwiener, D.; Beyer, Ines; Niederacher, Dieter; Fehm, Tanja; Templin, Markus F.; Neubauer, Hans

doi:10.1158/1541-7786.mcr-19-0141

Cited by 13 publications

(10 citation statements)

References 32 publications

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“…Currently, the mainstay for treatment of advanced EOC is tumor debulking surgery followed by a combination of platinum-based combination chemotherapy (usually for six cycles), with a platinum (carboplatin or cisplatin/CDDP) and a taxane (paclitaxel/PTX or docetaxel/DTX). Compared to other chemotherapeutic agents, PTX exhibits high tolerability, decreases hematological toxicities and neutropenia, thereby leading to an increase in the duration of the progression-free interval and overall survival (9). PTX is less myelosuppressive than DTX (10).…”

Section: Introductionmentioning

confidence: 99%

Role of hsa‑miR‑105 during the pathogenesis of paclitaxel resistance and its clinical implication in ovarian cancer

Mao

Zhang

et al. 2021

Oncol Rep

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More than 70% of patients with epithelial ovarian cancer (EOC), one of the leading cause of gynecological cancer-related deaths worldwide, are diagnosed at an advanced stage of the disease. Currently, the mainstay for treatment of advanced EOC is tumor debulking surgery followed by combined platinum-and paclitaxel (PTX)-based chemotherapy. However, most patients eventually develop chemoresistance, which remains a major obstacle to successful treatment. Herein, by using clinical specimens and experimentally induced cell models, we found that the expression levels of hsa-miR-105 were significantly decreased in PTX-resistant EOC tissues and cell lines. Follow-up functional experiments demonstrated that repression of hsa-miR-105 conferred resistance to paclitaxel in EOC cells, whereas restoration of hsa-miR-105 expression in situ via intratumoral injection of hsa-miR-105 micrON™ agomir potentiated in vivo sensitivity to PTX and thereafter significantly inhibited tumor growth in a PTX-challenged xenograft model. Mechanistically, hsa-miR-105 exerted its tumor suppressor function by directly inhibiting the zinc and ring finger 2 (ZNRF2) signaling pathway. Importantly, aberrant expression of hsa-miR-105 in both tumor and circulating samples predicted a poor post-chemotherapy prognosis in EOC patients. These findings collectively suggest that hsa-miR-105 may act as a potent tumor suppressor miRNA during the progression of EOC, likely affecting cell proliferation, invasiveness and chemosensitivity to PTX, and functioning at least in part via inhibition of ZNRF2 signaling. The stability and availability and ease in measurement of circulating hsa-miR-105 make it a valuable diagnostic/prognostic biomarker candidate for chemotherapy of EOC.

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Section: Introductionmentioning

confidence: 99%

Role of hsa‑miR‑105 during the pathogenesis of paclitaxel resistance and its clinical implication in ovarian cancer

Mao

Zhang

et al. 2021

Oncol Rep

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“…For comparison, in the stage-adjusted cohort of highgrade cancers with lower EZH2 expression, the rate of platinum-hypersensitivity was as low as 17.5% (data not shown). In accordance, loss of EZH2 has been recently described to drive resistance to carboplatin and paclitaxel in serous OCs provided ATM is upregulated 44 . These findings should give cause for concern regarding an indiscriminative use of EZH2 inhibitors combined with platinum-based chemotherapy in OC patients.…”

Section: Discussionmentioning

confidence: 65%

“…EZH2 is a good example showing that a biomarker can change its prognostic attributes with the levels of its expression in the same tumor entity. Such conversions may be dependent on a specific molecular context in the concerned cancers, for instance regarding EZH2 this could be either a concomitant overexpression of ATM or changing features in the interplay with Rev7 29,44 .…”

Section: Discussionmentioning

confidence: 99%

Clinical impact of EZH2 and its antagonist SMARCA4 in ovarian cancer

Leitner

Tsibulak

Wieser

et al. 2020

Sci Rep

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SMARCA4 and EZH2 are two functional key players of their respective antagonizing chromatin remodeling complexes SWI/SNF and PRC2. EZH2 inhibitory drugs may abrogate pro-oncogenic features of PRC2 and turn the balance to cell differentiation via SWI/SNF activity in cancers. SMARCA4 and EZH2 expression was assessed by RT-PCR in 238 epithelial ovarian cancers (OCs) and put in relation to clinico-pathological parameters and patients’ outcome. Optimal thresholds for high and low expression of both variables were calculated by the Youden’s index based on receiver operating characteristic (ROC) curves. High SMARCA4 mRNA expression was independently associated with favorable progression-free survival (PFS) (P = 0.03) and overall survival (OS) (P = 0.018). As Youden’s threshold determination for EZH2 yielded a S-shaped ROC-curve, two cut-off points (29th and 94th percentile) predicting opposite features were defined. Whereas EZH2 mRNA levels beyond the 29th percentile independently predicted poor PFS (P = 0.034), Cox-regression in EZH2 transcripts above the 94th percentile revealed a conversion from unfavorable to favorable PFS and OS (P = 0.009 and P = 0.032, respectively). High SMARCA4 expression associates with improved survival, whereas moderate/high EZH2 expression predicts poor outcome, which converts to favorable survival in ultra-high expressing OCs. This small OC subgroup could be characterized by REV7-abrogated platinum hypersensitivity but concomitant PARP-inhibitor resistance.

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“…Since BRCA1-de cient cells experience higher levels of DNA damage due to lower DSB repair e ciency, we assume that those cells display an increased dependence on ATM function for survival. In ovarian cancer cells, EZH2 inhibition has been shown to induce ATM overactivity and cell cycle checkpoint activation (44). The combined inhibition of EZH2 and ATM could provoke an exacerbation of the intrinsic defect of HR-mediated DSB repair leading to apoptosis in BRCA1-de cient cells but not in BRCA1-pro cient cells.…”

Section: Discussionmentioning

confidence: 99%

EZH2 Inhibition Sensitizes BRCA1-Deficient Breast Cancer to Synthetic Lethal Therapy with ATM Inhibitors

Ratz

Brambillasca

Bartke

et al. 2021

Preprint

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Background: The majority of BRCA1-mutant breast cancers are characterized by a triple-negative phenotype (TNBC) and a basal-like molecular subtype, associated with aggressive clinical behavior. Current treatment options are limited, highlighting the need for the development of novel targeted therapies for this tumor subtype. Methods: Our group previously showed that EZH2 is functionally relevant in BRCA1-deficient breast tumors and blocking EZH2 enzymatic activity could be a potent treatment strategy. To validate the role of EZH2 as a therapeutic target and to identify new synergistic drug combinations, we performed a high-throughput drug combination screen in various cell lines derived from BRCA1-proficient and deficient - mouse mammary tumors. Results: We identified the combined inhibition of EZH2 and the proximal DNA damage response kinase ATM as a novel synthetic lethality-based therapy for the treatment of BRCA1-deficient breast tumors. We show that the combined treatment with the EZH2 inhibitor GSK126 and the ATM inhibitor AZD1390 led to reduced colony formation, increased genotoxic stress, and apoptosis-mediated cell death in BRCA1-deficient mammary tumor cells in vitro. These findings were corroborated by in vivo experiments showing that simultaneous inhibition of EZH2 and ATM significantly increased anti-tumor activity in mice bearing BRCA1-deficient mammary tumors. Conclusion: Taken together, we identified a synthetic lethal interaction between EZH2 and ATM and propose this synergistic interaction as a novel molecular combination for the treatment of BRCA1-mutant breast cancer.

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EZH2 Loss Drives Resistance to Carboplatin and Paclitaxel in Serous Ovarian Cancers Expressing ATM

Cited by 13 publications

References 32 publications

Role of hsa‑miR‑105 during the pathogenesis of paclitaxel resistance and its clinical implication in ovarian cancer

Role of hsa‑miR‑105 during the pathogenesis of paclitaxel resistance and its clinical implication in ovarian cancer

Clinical impact of EZH2 and its antagonist SMARCA4 in ovarian cancer

EZH2 Inhibition Sensitizes BRCA1-Deficient Breast Cancer to Synthetic Lethal Therapy with ATM Inhibitors

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