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

Dahl, Erika S.; Buj, Raquel; Leon, Kelly E.; Newell, Jordan M.; Bitler, Benjamin G.; Snyder, Nathaniel W.; Aird, Katherine M.

doi:10.1101/472613

Cited by 3 publications

(3 citation statements)

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“…Using two independent HGSOC cells carrying wildtype ATM ( cbioportal.com ), we found that inhibition of ATM using two small molecule inhibitors (KU60019 and AZD0156) synergized with fenofibrate in multiple HGSOC cell lines to decrease colony formation ( Figure 4 A, B). While cell death, as determined by 7AAD staining, was not affected ( Figure 4 C), we observed multiple senescence markers, including increased SA-β-Gal and PML bodies and decreased lamin B1 expression [ 18 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ] in the combination treated cells ( Figure 4 D, E). Together, these data demonstrate that the combination of ATM inhibition and fenofibrate treatment is synergistic in HGSOC through induction of senescence.…”

Section: Resultsmentioning

confidence: 87%

ATM inhibition synergizes with fenofibrate in high grade serous ovarian cancer cells

Chen

Buj

Dahl

et al. 2020

Heliyon

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While therapies targeting deficiencies in the homologous recombination (HR) pathway are emerging as the standard treatment for high grade serous ovarian cancer (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. We found that the HR gene Ataxia Telangiectasia Mutated (ATM) is wildtype and its activity is upregulated in HGSOC compared to normal fallopian tube tissue. Interestingly, multiple pathways related to metabolism are inversely correlated with ATM expression in HGSOC specimens, suggesting that combining ATM inhibition with metabolic drugs would be effective. Analysis of FDA-approved drugs from the Dependency Map demonstrated that ATM-low cells are more sensitive to fenofibrate, a PPARα agonist that affects multiple cellular metabolic pathways. Consistently, PPARα 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. Together, our results suggest that metabolic changes induced by ATM inhibitors are a potential target for the treatment of HGSOC.

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Section: Resultsmentioning

confidence: 87%

ATM inhibition synergizes with fenofibrate in high grade serous ovarian cancer cells

Chen

Buj

Dahl

et al. 2020

Heliyon

Self Cite

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“…Recent data from HGSOC patients suggest that senescence occurs in vivo after therapy and is associated with a better outcome (46). Indeed, other publications have also indicated that senescence is a beneficial therapeutic response (47,48,(60)(61)(62)(63). The mechanism of senescence induction by the combination of ATM inhibition and fenofibrate remains to be explored.…”

Section: Discussionmentioning

confidence: 99%

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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“…Cell survival assays: Cell survival in response to knockdowns and enzalutamide was assessed using crystal violet staining. The crystal violet staining protocol was used as previously described [19]. In brief, 1x10 4 cells were seeded per well in 100uL RPMI 1640 with L-glutamine in 10% fetal bovine serum and underwent described drug treatments with eight biological replicates.…”

Section: Quantitative Pcr (Qpcr): Total Rna Was Extracted From Cells mentioning

confidence: 99%

Identification of genes required for enzalutamide resistance in castration-resistant prostate cancer cellsin vitro

Kohrt

Awadallah

Phillips

et al. 2020

Preprint

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Castration-resistant prostate cancer can be treated with the anti-androgen enzalutamide, but responses and duration of response are variable. To identify genes that support enzalutamide resistance, we performed a short hairpin RNA (shRNA) screen in the bone-homing, castrationresistant prostate cancer cell line, C4-2B. We identified eleven genes (TFAP2C, CAD, SPDEF, EIF6, GABRG2, CDC37, PSMD12, COL5A2, AR, MAP3K11, and ACAT1), whose loss resulted in decreased cell survival in response to enzalutamide. To validate our screen, we performed transient knockdowns in C4-2B and 22Rv1 cells and evaluated cell survival in response to enzalutamide. Through these studies, we validated three genes (ACAT1, MAP3K11, and PSMD12) as supporters of enzalutamide resistance in vitro. Although ACAT1 expression is lower in metastatic castration-resistant prostate cancer samples versus primary prostate cancer samples, knockdown of ACAT1 was sufficient to reduce cell survival in C4-2B and 22Rv1 cells.MAP3K11 expression increases with Gleason grade, and the highest expression is observed in metastatic castration-resistant disease. Knockdown of MAP3K11 reduced cell survival and pharmacologic inhibition of MAP3K11 with CEP-1347 in combination with enzalutamide resulted in a dramatic increase in cell death. This was associated with decreased phosphorylation of AR-Serine650, which is required for maximal AR activation. Finally, while PSMD12 expression did not change during disease progression, knockdown of PSMD12 resulted in decreased AR and AR splice variant expression, likely contributing to the C4-2B and 22Rv1 decrease in cell survival.Our study has therefore identified at least three new supporters of enzalutamide resistance in castration-resistant prostate cancer cells in vitro. IntroductionEarly stage prostate cancer is an androgen-dependent disease, and advanced prostate cancer is largely treated with androgen deprivation therapy, which targets androgen receptor (AR). Inevitably, tumors progress to castration-resistant prostate cancer. In castration-resistant prostate cancer, AR signaling continues through multiple mechanisms including AR full length (AR-FL) over-expression, increases in androgen production, and induction of constitutively active AR splice variants (AR-V) [1]. Currently, abiraterone acetate and enzalutamide are standard therapies in metastatic castration-resistant prostate cancer [2, 3]. Enzalutamide is well tolerated and effective, extending castration-resistant prostate cancer patient survival by 5 months versus placebo after chemotherapy[4] and delaying initiation of chemotherapy by 18 months versus placebo [5]. Nevertheless, tumors progress to enzalutamide-resistant castration-resistant prostate cancer. How these tumors progress to resistance is an area of active investigation, but both AR-dependent and AR-independent mechanisms have been proposed.The purpose of our studies was to identify genes that support resistance to enzalutamide and identify gene products (proteins) that once targeted could re-sensitize tum...

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

Cited by 3 publications

References 72 publications

ATM inhibition synergizes with fenofibrate in high grade serous ovarian cancer cells

ATM inhibition synergizes with fenofibrate in high grade serous ovarian cancer cells

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

Identification of genes required for enzalutamide resistance in castration-resistant prostate cancer cellsin vitro

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