Functional characterization of a panel of high-grade serous ovarian cancer cell lines as representative experimental models of the disease

Haley, James A.; Tomar, Sunil; Pulliam, Nicholas; Xiong, Sen; Perkins, Susan M.; Karpf, Adam R.; Mitra, Sumegha; Nephew, Kenneth P.; Mitra, Anirban

doi:10.18632/oncotarget.9053

Cited by 66 publications

(80 citation statements)

References 25 publications

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“…To determine whether EGLN1 dependency was enriched in a specific subtype, we grouped the ovarian cancer cell lines by historical pathologic, molecular, and histologic subtypes ( Supplementary Table S5; adapted from refs. 31,34,36). We found that EGLN1 dependency was significantly enriched in ovarian clear cell carcinoma lines compared with every other ovarian subtype ( Fig.…”

Section: Egln1 Dependency Is Enriched In Ovarian Clear Cell Carcinomamentioning

confidence: 71%

“…S2C). Ovarian cancer represents a heterogeneous disease comprised of four major different subtypes (26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36). To determine whether EGLN1 dependency was enriched in a specific subtype, we grouped the ovarian cancer cell lines by historical pathologic, molecular, and histologic subtypes ( Supplementary Table S5; adapted from refs.…”

Section: Egln1 Dependency Is Enriched In Ovarian Clear Cell Carcinomamentioning

confidence: 99%

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Genome-Wide Interrogation of Human Cancers Identifies EGLN1 Dependency in Clear Cell Ovarian Cancers

Price

Gill

et al. 2019

Cancer Research

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We hypothesized that candidate dependencies for which there are small molecules that are either approved or in advanced development for a nononcology indication may represent potential therapeutic targets. To test this hypothesis, we performed genome-scale loss-of-function screens in hundreds of cancer cell lines. We found that knockout of EGLN1, which encodes prolyl hydroxylase domain-containing protein 2 (PHD2), reduced the proliferation of a subset of clear cell ovarian cancer cell lines in vitro. EGLN1-dependent cells exhibited sensitivity to the pan-EGLN inhibitor FG-4592. The response to FG-4592 was reversed by deletion of HIF1A, demonstrating that EGLN1 dependency was related to negative regulation of HIF1A. We also found that ovarian clear cell tumors susceptible to both genetic and pharmacologic inhibition of EGLN1 required intact HIF1A. Collectively, these observations identify EGLN1 as a cancer target with therapeutic potential.Significance: These findings reveal a differential dependency of clear cell ovarian cancers on EGLN1, thus identifying EGLN1 as a potential therapeutic target in clear cell ovarian cancer patients.

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Section: Egln1 Dependency Is Enriched In Ovarian Clear Cell Carcinomamentioning

confidence: 71%

Section: Egln1 Dependency Is Enriched In Ovarian Clear Cell Carcinomamentioning

confidence: 99%

Genome-Wide Interrogation of Human Cancers Identifies EGLN1 Dependency in Clear Cell Ovarian Cancers

Price

Gill

et al. 2019

Cancer Research

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“…Shultz and coworkers recently identified a subset of OC cells that — in contrast to lines often employed — more closely resembles the copy‐number changes, mutations, and mRNA expression profiles presented by high‐grade serous ovarian tumors. We and others later identified cell lines among these whose phenotypic and histopathological features, in vivo, further aligned with that of the human disease. In these studies, we selected the OVCAR8 cell line due to its relatively aggressive growth rate, strongly mesenchymal phenotype, ability to form intraperitoneal tumors with high‐grade histopathological features, and murine disease accompaniment by ascitic fluid accumulation.…”

Section: Resultsmentioning

confidence: 80%

“…Chemotherapeutic drugs, cumulative stoichiometric ratios, and excipients employed here were consistent with current National Comprehensive Cancer Network (NCCN) treatment guidelines for intraperitoneal OC chemotherapy (stages II–IV). A relatively modest dose of cisplatin was used in this case as OVCAR8 is a platinum‐sensitive cell line.…”

Section: Resultsmentioning

confidence: 99%

RNA‐Peptide nanoplexes drug DNA damage pathways in high‐grade serous ovarian tumors

Dreaden

Kong

Quadir

et al. 2018

Bioengineering & Transla Med

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DNA damaging chemotherapy is a cornerstone of current front‐line treatments for advanced ovarian cancer (OC). Despite the fact that a majority of these patients initially respond to therapy, most will relapse with chemo‐resistant disease; therefore, adjuvant treatments that synergize with DNA‐damaging chemotherapy could improve treatment outcomes and survival in patients with this deadly disease. Here, we report the development of a nanoscale peptide‐nucleic acid complex that facilitates tumor‐specific RNA interference therapy to chemosensitize advanced ovarian tumors to frontline platinum/taxane therapy. We found that the nanoplex‐mediated silencing of the protein kinase, MK2, profoundly sensitized mouse models of high‐grade serous OC to cytotoxic chemotherapy by blocking p38/MK2‐dependent cell cycle checkpoint maintenance. Combined RNAi therapy improved overall survival by 37% compared with platinum/taxane chemotherapy alone and decreased metastatic spread to the lungs without observable toxic side effects. These findings suggest (a) that peptide nanoplexes can serve as safe and effective delivery vectors for siRNA and (b) that combined inhibition of MK2 could improve treatment outcomes in patients currently receiving frontline chemotherapy for advanced OC.

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“…MEK1/2-ERK1/2 signaling inhibition in ovarian cancer cells is reported to sensitize them to chemotherapy [47], so MEK1/2 pathway hyperactivation could be a mechanism allowing HGSOC cells to overcome cytotoxic effects of cisplatin. Cisplatin-induced MEK1/2 activation in OVCAR8 and PEO4 cell lines established from recurrent tumors, which already obtained cisplatin resistance [52][53][54], suggests that repeated cisplatin treatment can further promote MEK1/2-ERK1/2 activity and associated chemoresistance in HGSOC.…”

Section: Discussionmentioning

confidence: 99%

The MEK1/2 pathway as a therapeutic target in high-grade serous ovarian carcinoma

Chesnokov

Khan

Park

et al. 2019

Preprint

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Rationale: High-grade serous ovarian carcinoma (HGSOC) is the deadliest of gynecological cancers due to high rate of recurrence and acquired chemoresistance. Mutation and activation of the RAS/MAPK pathway has been linked to cancer cell proliferation and therapeutic resistance in numerous cancers. While RAS mutations are not commonly observed in HGSOC, less is known about downstream pathway activation. We therefore sought to investigate the role of MEK1/2 signaling in ovarian cancer.Methods: MEK1/2 pathway activity was evaluated in clinical HGSOC tissue samples and ovarian cancer cell lines by using tissue microarray-based immunohistochemistry, immunoblotting, and RT-qPCR. OVCAR8 and PEO4 HGSOC cell lines were used to assess the effect of MEK1/2 inhibition on cell viability, proliferation rate, and stem-like characteristics. Xenografts were used in mice to investigate the effect of MEK1/2 inhibition on tumor growth in vivo. A drug washout experimental model was used to study the lasting effects of MEK1/2 inhibition therapy.Results: MEK1/2 signaling is active in a majority of HGSOC tissue samples and cell lines. MEK1/2 is further stimulated by cisplatin treatment, suggesting that MEK1/2 activation may play a role in chemotherapy resistance. The MEK1/2 inhibitor, trametinib, drastically inhibits MEK1/2 downstream signaling activity, causes prominent cell cycle arrest in the G1/0-phase in cell cultures, and reduces the rate of tumor growth in vivo, but does not induce cell death. Cells treated with trametinib display a high CD133 + fraction and increased expression of stemness-associated genes.Transient trametinib treatment causes long-term increases in a high ALDH1 activity subpopulation of cells that possess the capability of surviving and growing in non-adherent conditions. Conclusions: MEK1/2 inhibition in HGSOC cells efficiently inhibits proliferation and tumorgrowth and therefore may be a promising approach to suppress ovarian cancer cell growth. MEK1/2 inhibition promotes stem-like properties, thus suggesting a possible mechanism of resistance and that a combination with CSC-targeting drugs should be considered.

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Functional characterization of a panel of high-grade serous ovarian cancer cell lines as representative experimental models of the disease

Cited by 66 publications

References 25 publications

Genome-Wide Interrogation of Human Cancers Identifies EGLN1 Dependency in Clear Cell Ovarian Cancers

Genome-Wide Interrogation of Human Cancers Identifies EGLN1 Dependency in Clear Cell Ovarian Cancers

RNA‐Peptide nanoplexes drug DNA damage pathways in high‐grade serous ovarian tumors

The MEK1/2 pathway as a therapeutic target in high-grade serous ovarian carcinoma

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