Abstract
Simple SummaryCarboplatin and paclitaxel constitute first-line treatment for ovarian cancer, producing tumor shrinkage in 70% of patients, but curing less than 20% with advanced stage disease. Previous studies have shown that treatment with ARN-3261, a small molecule inhibitor of the enzyme salt-induced kinase 2, can improve the response to paclitaxel in human ovarian cancer cells grown in culture and in immunocompromised mice. Here we have found that ARN-3261 also increases carboplatin’s ability to kill ovarian cancer cells grown in culture and in immunocompromised mice, causing additional DNA damage and decreasing levels of survivin, a protein that protects cancer cells from programmed cell death. Our studies encourage clinical evaluation of ARN-3261 and a Phase I clinical trial has been initiated to test the drug in ovarian cancer patients.Salt-induced kinase 2 (SIK2) is a serine-threonine kinase that regulates centrosome splitting, activation of PI3 kinase and phosphorylation of class IIa HDACs, affecting gene expression. Previously, we found that inhibition of SIK2 enhanced sensitivity of ovarian cancer cells to paclitaxel. Carboplatin and paclitaxel constitute first-line therapy for most patients with ovarian carcinoma, producing a 70% clinical response rate, but curing <20% of patients with advanced disease. We have asked whether inhibition of SIK2 with ARN-3261 enhances sensitivity to carboplatin in ovarian cancer cell lines and xenograft models. ARN-3261-induced DNA damage and apoptosis were measured with γ-H2AX accumulation, comet assays, and annexin V. ARN-3261 inhibited growth of eight ovarian cancer cell lines at an IC50 of 0.8 to 3.5 µM. ARN-3261 significantly enhanced sensitivity to carboplatin in seven of eight ovarian cancer cell lines and a carboplatin-resistant cell line tested. Furthermore, ARN-3261 in combination with carboplatin produced greater inhibition of tumor growth than carboplatin alone in SKOv3 and OVCAR8 ovarian cancer xenograft models. ARN-3261 enhanced DNA damage and apoptosis by downregulating expression of survivin. Thus, a SIK2 kinase inhibitor enhanced carboplatin-induced therapy in preclinical models of ovarian cancer and deserves further evaluation in clinical trials.
Highlights
Ovarian cancer is a leading cause of gynecological cancer death
To determine whether ARN-3261 could inhibit the growth of ovarian cancer cells, the effect of ARN-3261 was measured in eight ovarian cancer cell lines using short term cell proliferation assays
When ARN-3261 was added to carboplatin, the carboplatin dose response curve was shifted to the left in seven of eight ovarian cancer cell lines (Figure 1C), indicating that ARN-3261 sensitizes ovarian cancer cells to carboplatin (p < 0.01)
Summary
Ovarian cancer is a leading cause of gynecological cancer death. Each year, 230,000 women will be diagnosed with ovarian cancer and 150,000 will die from the disease worldwide [1]. Our group has sought kinases that regulate the response of ovarian cancer cells to paclitaxel and carboplatin and whose inhibition might improve outcomes for women with ovarian cancer [3]. One of the most promising targets to date is salt-induced kinase 2 (SIK2) which is overexpressed in 30% of ovarian cancers, associated with decreased progression-free survival [4]. ARN-3261, a clinical lead compound derived from ARN-3236 by introducing a solvent binding sulfone, showed acceptable profiles in cell-based proliferation assays, ADME and in PK/PD studies and resisted efflux through the P-gp transporter. Inhibition of SIK2 with ARN-3236 enhanced the sensitivity of ovarian cancer cells to paclitaxel in cell culture and in xenografts [14]. In this report we have asked whether ARN-3261 could increase DNA damage and enhance response to carboplatin
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