Abstract
Molecular targeted therapies have been the focus of recent clinical trials for the treatment of patients with recurrent epithelial ovarian cancer (EOC). The majority have not fared well as monotherapies for improving survival of these patients. Poor bioavailability, lack of predictive biomarkers, and the presence of multiple survival pathways can all diminish the success of a targeted agent. Dasatinib is a tyrosine kinase inhibitor of the Src-family kinases (SFK) and in preclinical studies shown to have substantial activity in EOC. However, when evaluated in a phase 2 clinical trial for patients with recurrent or persistent EOC, it was found to have minimal activity. We hypothesized that synthetic lethality screens performed using a cogently designed siRNA library would identify second-site molecular targets that could synergize with SFK inhibition and improve dasatinib efficacy. Using a systematic approach, we performed primary siRNA screening using a library focused on 638 genes corresponding to a network centered on EGFR, HER2, and the SFK-scaffolding proteins BCAR1, NEDD9, and EFS to screen EOC cells in combination with dasatinib. We followed up with validation studies including deconvolution screening, quantitative PCR to confirm effective gene silencing, correlation of gene expression with dasatinib sensitivity, and assessment of the clinical relevance of hits using TCGA ovarian cancer data. A refined list of five candidates (CSNK2A1, DAG1, GRB2, PRKCE, and VAV1) was identified as showing the greatest potential for improving sensitivity to dasatinib in EOC. Of these, CSNK2A1, which codes for the catalytic alpha subunit of protein kinase CK2, was selected for additional evaluation. Synergistic activity of the clinically relevant inhibitor of CK2, CX-4945, with dasatinib in reducing cell proliferation and increasing apoptosis was observed across multiple EOC cell lines. This overall approach to improving drug efficacy can be applied to other targeted agents that have similarly shown poor clinical activity.
Highlights
Ovarian cancer is the second most common gynecological cancer afflicting women in the United States [1]
We chose this library because it targeted many of the signaling proteins which act upstream, downstream, or in parallel with Src-family kinases (SFK), given its interplay with receptor tyrosine kinases (RTKs) [34, 35] and its prominent role in facilitating signal transduction from RTKs [17,18,19], providing us with the most relevant and likely candidates to target in combination with inhibition of SFK
As we have previously reported, it showed a limited response as a single agent in previously treated patients with recurrent epithelial ovarian cancer (EOC) [27], it is a potent inhibitor of the SRC family and BCR-ABL tyrosine kinases that is well tolerated by patients and for which our studies provide preclinical rationale to evaluate in combination with other targeted agents
Summary
Ovarian cancer is the second most common gynecological cancer afflicting women in the United States [1]. There are three main types of ovarian tumors classified based on their tissue of origin (surface epithelium, stromal endocrine cells, and germ cells), with epithelial carcinomas accounting for >90% of ovarian malignancies [2]. These epithelial tumors are generally further divided based on their cellular morphology, the four most common subtypes being serous, endometrioid, clear cell, and mucinous, with each subtype having different pathogenesis, chemo sensitivities, and prognoses [2, 3]. Despite favorable response rates to this initial treatment, ~75% of the patients eventually experience a recurrence of a tumor that becomes treatment-resistant. As additional molecular characterizations of disease subtypes and a better understanding of their clinical biology and predictive biomarkers become available, personalized medicine can be provided to improve patient outcomes through the inclusion of targeted therapies [3,4,5,6]
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