Cellular senescence is a central response to cytotoxic chemotherapy in high-grade serous ovarian cancer

Calvo, L.; Cheng, Su Chun; Skulimowski, M.; Clément, I; Portelance, Lise; Zhan, Yanhu; Carmona, Eurı́dice; Lafontaine, Julie; Ladurantaye, Manon de; Rahimi, Kurosh; Provencher, Diane; Mes‐Masson, Anne‐Marie

doi:10.1101/425199

Cited by 8 publications

(15 citation statements)

References 83 publications

(99 reference statements)

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“…S3C), suggesting that targeting IDH1 may lead to a sustained cell cycle arrest and therapeutic response. Our results in addition to others suggest that senescence induction in the cell-type specific context of ovarian cancer may overall be tumorsuppressing (17,19,83). Altogether, we propose that targeting IDH1 may act as a novel pro-senescent therapy for HGSC patients.…”

Section: Discussionsupporting

confidence: 78%

“…Senescence is considered a tumor suppressive mechanism, and senescence induction is considered a beneficial therapeutic outcome (16,19,81). However, senescence may also promote cancer through the senescence-associated secretory phenotype (SASP), which increases inflammation and alters the surrounding microenvironment milieu (82).…”

Section: Discussionmentioning

confidence: 99%

“…Due to the decrease in proliferation, therapy-induced senescence is considered a desirable therapeutic outcome (16)(17)(18). Interestingly, recent evidence suggests that therapy-induced senescence leads to a better 5-year survival rate for HGSC patients (19).…”

Section: Introductionmentioning

confidence: 99%

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Targeting IDH1 as a pro-senescent therapy in high-grade serous ovarian cancer

Dahl

Buj

Leon

et al. 2018

Preprint

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Epithelial ovarian cancer (EOC) is the deadliest gynecological cancer. High-grade serous carcinoma (HGSC) is the most frequently diagnosed and lethal histosubtype of EOC. A significant proportion of HGSC patients relapse with chemoresistant disease.Therefore, there is an urgent need for novel therapeutic strategies for HGSC. Metabolic reprogramming is a hallmark of cancer cells, and targeting metabolism for cancer therapy may be beneficial. Here we found that in comparison to normal fallopian tube epithelial cells, HGSC cells preferentially utilize glucose in the TCA cycle and not for aerobic glycolysis. This correlated with universally increased TCA cycle enzyme expression in HGSC cells under adherent conditions. To further differentiate the necessity of TCA cycle enzymes in ovarian cancer progression, we found that only wildtype isocitrate dehydrogenase I (IDH1) is both significantly increased in HGSC cells in spheroid conditions and is associated with reduced progression-free survival. IDH1 protein expression is also increased in primary HGSC patient tumors. Pharmacological inhibition or knockdown of IDH1 decreased proliferation of multiple HGSC cell lines by inducing senescence. Mechanistically, suppression of IDH1 increased the repressive histone mark H3K9me2 at proliferation promoting gene loci (PCNA and MCM3), which led to decreased mRNA expression. Altogether, these data suggest that increased IDH1 activity is an important metabolic adaptation in HGSC and that targeting wildtype IDH1 in HGSC alters the repressive histone epigenetic landscape to induce senescence.Therefore, inhibition of IDH1 may act as a novel therapeutic approach to alter both the metabolism and epigenetics of HGSC as a pro-senescent therapy.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

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Targeting IDH1 as a pro-senescent therapy in high-grade serous ovarian cancer

Dahl

Buj

Leon

et al. 2018

Preprint

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“…Cellular senescence has been reported to be a central response to cytotoxic chemotherapy in HGSC 25 . Indeed, we observed that a key cellular response of HGSC to CX-5461 plus topotecan is a G2/M cell cycle arrest and a senescence-like phenotype, which occurs through an enhanced nucleolar DDR without DNA resection.…”

Section: Discussionmentioning

confidence: 99%

Targeting RNA Polymerase I transcription synergises with TOP1 inhibition in potentiating the DNA damage response in high-grade serous ovarian cancer

Yan

Madhamshettiwar

Simpson

et al. 2019

Preprint

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Limited effective therapeutic options are available for patients with recurrent highgrade serous carcinoma (HGSC), the most common histological subtype accounting for the majority of ovarian cancer deaths. We have shown efficacy in poly-ADP ribose polymerase (PARP) inhibitor-resistant HGSC for the RNA Polymerase I (Pol I) transcription inhibitor CX-5461 through its ability to activate a nucleolar-associated DNA damage response (DDR). Here, we screen the protein-coding genome to identify potential targets whose inhibition enhances the efficacy of CX-5461. We identify a network of cooperating inhibitory interactions, including components of homologous recombination (HR) DNA repair and DNA topoisomerase 1 (TOP1). We highlight that CX-5461 combined with topotecan, a TOP1 inhibitor used as salvage therapy in HGSC, induces robust cell cycle arrest and cell death in a panel of HRproficient HGSC cell lines. The combination potentiates a nucleolar-associated DDR via recruitment of phosphorylated replication protein A (RPA) and ataxia telangiectasia and Rad3 related protein (ATR). CX-5461 plus low-dose topotecan cooperate to potently inhibit xenograft tumour growth, indicating the potential for this strategy to improve salvage therapeutic regimens to treat HGSC.

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“…This may be due in part to upregulation of multiple metabolic pathways in ATM-low cancers. The combination induced senescence, a stable cell cycle arrest that is considered a positive patient outcome (46)(47)(48). Together, our results provide rationale for exploration of drugs that modify metabolism as combinatorial therapies with ATM inhibitors.…”

Section: Discussionmentioning

confidence: 67%

ATM Inhibition Synergizes with Fenofibrate in High Grade Serous Ovarian Cancer Cells

Chen

Buj

Dahl

et al. 2020

Preprint

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Background: Epithelial ovarian cancer (EOC) is the deadliest gynecological malignancy in the United States with high grade serous ovarian cancer (HGSOC) as the most commonly diagnosed subtype. While therapies targeting deficiencies in the homologous recombination (HR) pathway are emerging as the standard treatment for HGSOC patients, this strategy is limited to the 50% of patients with a deficiency in this pathway. Therefore, patients with HR-proficient tumors are likely to be resistant to these therapies and require alternative strategies. Methods:Data from HGSOC patients in The Cancer Genome Atlas (TCGA) were analyzed for ATM status, ATM and PPARa expression, and used to perform Gene Set Enrichment Analysis (GSEA). Screening data from the Dependency Map were analyzed to identify FDA-approved drugs that preferentially inhibit ATM-low cancer cells. In vitro studies were performed to determine whether ATM inhibitors synergize with the PPARa agonist fenofibrate in HGSOC cell lines. Results:The HR gene Ataxia Telangiectasia Mutated (ATM) is wildtype in the majority of HGSOC patients and its kinase activity is upregulated compared to normal fallopian tube tissue. As high ATM has been associated with poor overall and progression-free survival, targeting ATM may be beneficial for a subset of HGSOC patients. Clinical trials of ATM inhibitors are commencing; however, ATM inhibitors are not effective as single agents. We aimed to explore novel therapeutic vulnerabilities of ATM deficient cells to develop a combinatorial therapy. Using data from TCGA, we found that multiple pathways related to metabolism are inversely correlated with ATM expression, suggesting that combining ATM inhibition and metabolic inhibition would be effective. Indeed, analysis of FDA-approved drugs from the Dependency Map demonstrated that ATM low cell lines are more sensitive to fenofibrate, a PPARa agonist that has been previously shown to affect multiple cellular metabolic pathways. Consistently, PPARa signaling is associated with ATM expression. We validated that combined inhibition of ATM and treatment with fenofibrate is synergistic in multiple HGSOC cell lines by inducing senescence. Conclusions:Our results suggest that metabolic changes induced by ATM inhibitors are a potential target for the treatment for HGSOC.

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Cellular senescence is a central response to cytotoxic chemotherapy in high-grade serous ovarian cancer

Cited by 8 publications

References 83 publications

Targeting IDH1 as a pro-senescent therapy in high-grade serous ovarian cancer

Targeting IDH1 as a pro-senescent therapy in high-grade serous ovarian cancer

Targeting RNA Polymerase I transcription synergises with TOP1 inhibition in potentiating the DNA damage response in high-grade serous ovarian cancer

ATM Inhibition Synergizes with Fenofibrate in High Grade Serous Ovarian Cancer Cells

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