Journal
CANCER CELL
Volume 28, Issue 1, Pages 82-96Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2015.05.009
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Funding
- NCI's Clinical Proteomic Tumor Analysis Consortium (CPTAC) initiative [U24CA160036]
- Conquer Cancer Foundation Young Investigator Award
- HERA OSB Grant from the HERA Women's Cancer Foundation
- Ovarian Cancer Research Fund [292512]
- [RO1CA103937]
- [W81XWH-11-2-0230/OC100517]
- [RO1CA148826]
- [R21CA187512]
- [R01CA174388]
- [U54CA143868]
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Resistance to chemotherapy represents a major obstacle for long-term remission, and effective strategies to overcome drug resistance would have significant clinical impact. We report that recurrent ovarian carcinomas after paclitaxel/carboplatin treatment have higher levels of spleen tyrosine kinase (SYK) and phospho-SYK. In vitro, paclitaxel-resistant cells expressed higher SYK, and the ratio of phospho-SYK/SYK positively associated with paclitaxel resistance in ovarian cancer cells. Inactivation of SYK by inhibitors or gene knockdown sensitized paclitaxel cytotoxicity in vitro and in vivo. Analysis of the phosphotyrosine proteome in paclitaxel-resistant tumor cells revealed that SYK phosphorylates tubulins and microtubule-associated proteins. Inhibition of SYK enhanced microtubule stability in paclitaxel-resistant tumor cells that were otherwise insensitive. Thus, targeting SYK pathway is a promising strategy to enhance paclitaxel response.
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