Abstract
Simple SummaryIn ovarian cancer patients the PI3K/AKT/mTOR and RAS/RAF/MEK/ERK kinase signaling pathways are frequently dysregulated, making them potential targets of therapeutic inhibitors. In this study, we used four human ovarian cancer cell lines grown in two- and three-dimensional models to investigate the potential efficacy of combining two inhibitors, which target these pathways, against ovarian cancer. The inhibitor combination was found to have cell line- and model-dependent synergistic antiproliferative effect.Most ovarian cancer patients are diagnosed with advanced stage disease, which becomes unresponsive to chemotherapeutic treatments. The PI3K/AKT/mTOR and the RAS/RAF/MEK/ERK kinase signaling pathways are attractive targets for potential therapeutic inhibitors, due to the high frequency of mutations to PTEN, PIK3CA, KRAS and BRAF in several ovarian cancer subtypes. However, monotherapies targeting one of these pathways have shown modest effects in clinical trials. This limited efficacy of the agents could be due to upregulation and increased signaling via the adjacent alternative pathway. In this study, the efficacy of combined PI3K/mTOR (BEZ235) and ERK inhibition (SCH772984) was investigated in four human ovarian cancer cell lines, grown as monolayer and three-dimensional cell aggregates. The inhibitor combination reduced cellular proliferation in a synergistic manner in OV-90 and OVCAR8 monolayers and in OV-90, OVCAR5 and SKOV3 aggregates. Sensitivity to the inhibitors was reduced in three-dimensional cell aggregates in comparison to monolayers. OV-90 cells cultured in large spheroids were sensitive to the inhibitors and displayed a robust synergistic antiproliferative response to the inhibitor combination. In contrast, OVCAR8 spheroids were resistant to the inhibitors. These findings suggest that combined PI3K/mTOR and ERK inhibition could be a useful strategy for overcoming treatment resistance in ovarian cancer and warrants further preclinical investigation. Additionally, in some cell lines the use of different three-dimensional models can influence cell line sensitivity to PI3K/mTOR and RAS/RAF/MEK/ERK pathway inhibitors.
Highlights
This article is an open access articleOvarian cancer is a deadly disease that has a five-year survival rate below 50% [1]. ovarian cancer mortality has decreased due to a reduction in incidence (10 deaths per 100,000 in 1976 to 6.7 per 100,000 in 2015), the five-year survival rates have changed little in the past few decades [1]
To investigate the effect of the dual PI3K/mechanistic target of rapamycin (mTOR) inhibitor BEZ235 on cell viability, OV-90, OVCAR8, OVCAR5 and SKOV3 cells were cultured for 48 h as both monolayers and cell aggregates and exposed to the inhibitor for 72 h
While the aggregate and spheroid models used in this present study are likely to be more representative of tumor response, co-culture with stromal cells or the inclusion of ECM-mimicking hydrogels is likely to further impact the efficacy of these inhibitors through changes in gene expression [50]. This maybe relevant with the use of ovarian cancer ex vivo 3D models to predict clinical response to chemotherapies being investigated [81]. This present study investigated the novel combination of PI3K/mTOR and ERK
Summary
This article is an open access articleOvarian cancer is a deadly disease that has a five-year survival rate below 50% [1]. ovarian cancer mortality has decreased due to a reduction in incidence (10 deaths per 100,000 in 1976 to 6.7 per 100,000 in 2015), the five-year survival rates have changed little in the past few decades [1]. Mutations within the PI3K/AKT/mTOR and RAS/RAF/MEK/ERK kinase signaling pathways are characteristic of the low-grade serous (LGSOC), mucinous (MOC), endometrioid (ENOC) and clear cell (CCOC) ovarian cancer subtypes [4,5,6,7]. Both of these pathways play critical roles in normal healthy cells and their dysregulation can result in excessive proliferation and cell survival [8,9,10]. Upregulation of these pathways has been implicated in the evasion of anoikis, the loss of adhesion and the promotion of invasion, enabling intraperitoneal metastasis [11,12,13,14]
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