Abstract 3496: SYK inhibition results in increased sensitivity of OVCAR-3 cells to paclitaxel

Abstract

In order to identify novel drug targets in ovarian cancers, we examined our ovarian cancer gene expression microarray data for expression of genes in the tyrosine kinase family. The spleen tyrosine kinase (SYK) gene was expressed in 73% of 55 ovarian cancer specimens, compared to 26% of 60 breast cancer specimens. Previous studies established the role of SYK in lymphocyte development, immune cell activation, and tumor progression. We found SYK to be expressed in 6 of 10 ovarian carcinoma cell lines. Among its many targets, SYK can bind microtubules and other molecules associated with the cytoskeleton. Because of this ability, we studied the relationship of SYK expression to cellular sensitivity to taxanes. We focused on the OVCAR-3 cell line, which was one of the highest SYK-expressing cell lines, to elucidate the potential effects of SYK on taxane sensitivity. Our results demonstrate that knockdown of SYK expression by siRNA resulted in a one log-fold increased sensitivity of OVCAR-3 cells to the taxane, paclitaxel. Furthermore, this effect was durable, as knockdown of SYK and sensitization to paclitaxel persisted over 128 hours. The potential effects of SYK on tubulin polymerization are currently being investigated. We will evaluate potential upstream and downstream targets to elucidate the pathway(s) responsible for SYK effects and determine whether SYK levels contribute to tumor resistance to chemotherapeutic agents. Understanding the growth signals in drug sensitive and resistant ovarian cancer cell lines and tumor samples may eventually lead to new therapeutic approaches for ovarian cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3496.

Effect of dasatinib against thyroid cancer cell lines in vitro and a xenograft model in vivo

“…4A: microarray data from Oncomine). At present, the data available on the role of Syk in solid malignancies remain unclear although it has paradoxically been reported to be a potential oncogene in ovarian cancer (23) and a tumor suppressor in breast cancer (24). Our finding that the Syk protein is highly expressed in thyroid cancer and is decreased by dasatinib treatment suggests it may be an oncogene in thyroid cancer.…”