Abstract
Inactivation of SYK synergistically increases paclitaxel sensitivity in ovarian cancer cells.
Major finding: Inactivation of SYK synergistically increases paclitaxel sensitivity in ovarian cancer cells.
Mechanism: SYK inhibition in the presence of paclitaxel stabilizes microtubules in paclitaxel-resistant cells.
Impact: Dual treatment with SYK inhibitors may overcome paclitaxel resistance in recurrent ovarian cancer.
Patients with ovarian high-grade serous carcinoma (HGSC) initially respond to treatment with the chemotherapeutic agents carboplatin and paclitaxel, but frequently experience tumor relapse. However, the mechanisms underlying the development of resistance to these drugs remain poorly understood. Yu and colleagues found that the levels of spleen tyrosine kinase (SYK) and phosphorylated SYK were increased in recurrent ovarian tumors isolated from patients previously treated with carboplatin and paclitaxel compared with matched primary untreated tumors. In addition, SYK expression and activation were upregulated in paclitaxel-resistant ovarian cancer cell lines and positively correlated with paclitaxel response in vitro, suggesting that SYK overexpression may confer chemoresistance. SYK inactivation via knockdown or pharmacologic inhibition with the active metabolite of fostamatinib, R406, impaired the growth of ovarian cancer cells and synergistically enhanced the sensitivity of paclitaxel-resistant primary ovarian cancer cells and ovarian cancer cell lines to paclitaxel in vitro. Consistent with this finding, dual treatment with R406 and paclitaxel suppressed the growth of both naïve and paclitaxel-resistant ovarian tumor xenografts compared with single-agent treatment. Phosphoproteomic analysis in paclitaxel-resistant ovarian cancer cells identified substrate proteins phosphorylated by SYK, which were enriched in proteins implicated in cell growth pathways and cytoskeletal organization. In particular, SYK phosphorylated the microtubule components tubulin and the microtubule-associated proteins (MAP) MAP1B and MAP4; phosphorylation of these substrates was increased in paclitaxel-resistant cells and correlated with total and phosphorylated SYK levels in HGSC samples. Expression of an active SYK mutant enhanced MAP1B and MAP4 phosphorylation and was sufficient to confer paclitaxel resistance, whereas inhibition of SYK augmented paclitaxel-induced microtubule stabilization in paclitaxel-resistant ovarian cancer cells. These findings provide preclinical evidence for targeting SYK in ovarian cancer and suggest that SYK inhibition may enhance treatment response and overcome paclitaxel resistance in patients with HGSC.
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