SYK overexpression enhances microtubule instability in an MDA-MB-231-derived paclitaxel-resistant cell line

Paclitaxel resistance is a major obstacle to achieving long-term remission in patients with triple-negative breast cancer (TNBC), and effective strategies to overcome drug resistance would have significant clinical impact. In this study, we established a paclitaxel-resistant cell clone, T50R, from the human TNBC cell line MDA-MD-231. Intriguingly, these drug-resistant T50R cells required paclitaxel for proliferation. When cultured in the absence of drug, the cells exhibited high dynamic instability of microtubules (MTs) and spindle abnormalities, causing their accumulation in mitosis phase and cell death. Thus, the increased instability of MTs in T50R cells may contribute to the drug requirement for cell growth and drug-resistant phenotype, as paclitaxel counteracts the effect. Compared to the parental MDA-MD-231 cells, T50R cells had elevated expression of spleen tyrosine kinase (SYK), and inhibition or depletion of SYK in the T50R cells cultured without paclitaxel restored MT stability, reduced spindle defects and rescued cell death, suggesting that SYK overexpression contributes to the enhanced MT instability in T50R cells. Furthermore, T50R cells exhibited signs of ER stress and underwent ferroptotic cell death when cultured without paclitaxel, both of which could be ameliorated by inhibition of SYK. Finally, small molecules that target SYK or induce ferroptosis could significantly enhance T50R cell sensitivity to paclitaxel. Together, our results show that SYK-enhanced MT dynamic instability can play an important role in paclitaxel resistance and that targeting the SYK pathway may enhance paclitaxel response.