Abstract
Simple SummaryThe outcome for women diagnosed with ovarian cancer (OC), the most aggressive gynecological tumor worldwide, remains very poor. Encouraging therapeutic impact of epigenetic drugs has been suggested in a wide range of human solid tumors, including OC. The present study assessed the in vitro cytostatic and cytotoxic effects of OTX015, a pan Bromodomain and Extra-Terminal motif inhibitor, in human OC cells, both as single treatment and in combination with radiotherapy. Cellular, molecular and computational network analyses indicated the centrality of GNL3 downregulation in mediating the OTX015-related antitumor efficacy that blocks disease progression/maintenance and radioresistance acquisition. Our preclinical results confirm that targeted and combinatorial treatments represent effective anticancer strategies to be translated in the clinical research for improving OC patient care.Ovarian cancer (OC) is the most aggressive gynecological tumor worldwide and, notwithstanding the increment in conventional treatments, many resistance mechanisms arise, this leading to cure failure and patient death. So, the use of novel adjuvant drugs able to counteract these pathways is urgently needed to improve patient overall survival. A growing interest is focused on epigenetic drugs for cancer therapy, such as Bromodomain and Extra-Terminal motif inhibitors (BETi). Here, we investigate the antitumor effects of OTX015, a novel BETi, as a single agent or in combination with ionizing radiation (IR) in OC cellular models. OTX015 treatment significantly reduced tumor cell proliferation by triggering cell cycle arrest and apoptosis that were linked to nucleolar stress and DNA damage. OTX015 impaired migration capacity and potentiated IR effects by reducing the expression of different drivers of cancer resistance mechanisms, including GNL3 gene, whose expression was found to be significantly higher in OC biopsies than in normal ovarian tissues. Gene specific knocking down and computational network analysis confirmed the centrality of GNL3 in OTX015-mediated OC antitumor effects. Altogether, our findings suggest OTX015 as an effective option to improve therapeutic strategies and overcome the development of resistant cancer cells in patients with OC.
Highlights
Ovarian cancer (OC) is a rare but highly lethal gynecologic malignancy, representing 3% of all tumors and the fifth leading cause of cancer mortality in women worldwide [1]
The antitumor effects of OTX015, a new pan Bromodomain and Extra Terminal (BET) inhibitor used in 1/2 phase clinical trials in different malignancies, have been assessed in ovarian cancer (OC) in vitro models, SKOV3 cells, representing an adenocarcinoma OC tumor, and UWB1.289 cells, deriving from a papillary serous histology OC tumor
Proliferation and viability of OC cells were significantly inhibited by OTX015 exposure in a dose-dependent manner, with IC50 values of about 1.5 μM, which are within the range of clinical relevance
Summary
Ovarian cancer (OC) is a rare but highly lethal gynecologic malignancy, representing 3% of all tumors and the fifth leading cause of cancer mortality in women worldwide [1]. This high death-to-incidence ratio is essentially due to the absence of OC-related specific symptoms and the lack of effective screening strategies, so many women are diagnosed at advanced stage of the disease, when cancer has already spread into the abdominal cavity [2]. Epigenetic modifications, which include DNA methylation, histone modifications, and post-transcriptional gene regulation by non-coding RNAs (ncRNAs), have increasingly been associated with the development, progression and response to therapies of different human cancers, including OC [6]. Aberrant expression of BRD4 has been frequently found in OC patients and it has been correlated with poor prognosis [10]
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