Abstract 4670: Combinations of kinase siRNAs potentiates paclitaxel sensitivity in ovarian cancer

• Published in: Cancer research (Chicago, Ill.) Ill.), 2016-07, Vol.76 (14_Supplement), p.4670-4670
• Main Authors: Yang, Hailing, Wang, Xiaoyan, Ahmed, Ahmed, Iles, Lakesla, Bartholomeusz, Geoffrey, Lu, Zhen, Bast, Robert C.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2016-4670

Drug resistance imposes a major obstacle in ovarian cancer treatment. All patients with newly diagnosed ovarian cancer are treated with a combination of paclitaxel and carboplatin. While 70% of ovarian cancers respond to carboplatin, less than 50% respond to paclitaxel. Inhibition of kinases that modulate primary paclitaxel resistance, could enhance response to therapy. A Kinase siRNA library was screened in ovarian cancer cell lines to determine which kinases regulate paclitaxel sensitivity. Among 45 hits from high throughput screening, 14 target proteins (AATK, ACRBP, BMP2K, CHUK, EDN2, IKBKB, ILK, RAPGEF3, RAPGEF4, RFP, SIK2, STK24, STK39 and TBK1) regulated sensitivity to paclitaxel and were differentially expressed or overexpressed in a fraction of ovarian cancers. siRNAs against each of these kinases were tested for the ability to enhance sensitivity to paclitaxel in each of 12 ovarian cancer cell lines that reflected the heterogeneity observed in ovarian cancers including mutations of TP53, BRCA1/2, KRAS, BRAF, PI3K and PTEN. Knockdown of 10 individual genes enhanced paclitaxel sensitivity by at least two folds in different cell lines. A subscreen using combinations of these 14 kinase siRNAs in the six most responsive cell lines were carried out to select pairs of kinase siRNAs which could further potentiate paclitaxel sensitivity. IKBKB and STK39 kinase siRNAs had the greatest activity. We discovered that knockdown of IKBKB and STK39 stabilized microtubules judged by a microtubule fractionation assay and levels of acetylated and detyrosinated tubulin. IKBKB and STK39 kinase siRNAs also induced apoptosis. Double knockdown of microtubule stabilizing kinases IKBKB and STK39 resulted in greater enhancement in microtubule stability and apoptosis, leading to additive sensitization of paclitaxel. Small molecule inhibitors are available for IKBKB. As inhibition drugs become available for STK39, these observations can be translated to the clinic. Citation Format: Hailing Yang, Xiaoyan Wang, Ahmed Ahmed, Lakesla Iles, Geoffrey Bartholomeusz, Zhen Lu, Robert C. Bast Jr.. Combinations of kinase siRNAs potentiates paclitaxel sensitivity in ovarian cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4670.