Tumor cell resistance to drug treatment severely limits the therapeutic success of treatment. Tumor cells, exposed to chemotherapeutic drugs, have developed intricate strategies to escape the cytotoxic effects and adapt to adverse conditions. The molecular mechanisms causing drug resistance can be based upon modifications of drug transport or metabolism, structural alterations of drug targets or adaptation of cellular signaling. An important component in the transformation of cells and the emergence of drug resistance is the activation of the transcription factor Stat3. The persistent, inappropriate activation of Stat3 causes the expression of target genes which promote tumor cell proliferation, survival, invasion and immune suppression, and it is instrumental in the process of the emergence of resistance to both conventional chemotherapeutic agents and novel targeted compounds. For these reasons, Stat3 inhibition is being pursued as a promising therapeutic strategy. We have investigated the effects of the tyrosine kinase inhibitor canertinib on the glioma cell line Tu-2449. In these cells Stat3 is persistently phosphorylated and activated downstream of the oncogenic driver v-Src and its effector, the cytoplasmic tyrosine kinase Bmx. Canertinib exposure of Tu-2449 cells rapidly caused the inhibition of the Bmx kinase and the deactivation of Stat3. Prolonged exposure of the cells to canertinib caused the death of the large majority of the cells. Only a few cells became resistant to canertinib and survived in tight clusters. These cells have become drug resistant. When the canertinib resistant cells were expanded and cultured at lower cell densities, they regained their sensitivity towards canertinib. We measured the extent of Stat3 activation as a function of cell density and found that higher cell densities are accompanied by increased Stat3 activation and a higher expression of Stat3 target genes. We suggest that Stat3 induction through tight cell-cell interactions, most likely through the engagement of cadherins, can counteract the inhibitory effects exerted by canertinib on Bmx. Cell-cell interactions induced Stat3 and compensated for the suppression of Stat3 by canertinib, thus transiently protecting the cells from the cytotoxic effects of the inhibitor.

中文翻译：

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肿瘤细胞对靶向疗法的抵抗力：培养的神经胶质瘤肿瘤细胞的密度增强了Stat3活性，并提供了针对酪氨酸激酶抑制剂canertinib的保护。

肿瘤细胞对药物治疗的抵抗力严重限制了治疗的治疗成功。暴露于化疗药物的肿瘤细胞已制定出复杂的策略，以逃避细胞毒作用并适应不利条件。引起耐药性的分子机制可以基于药物转运或代谢的改变，药物靶标的结构改变或细胞信号传导的适应。细胞转化和耐药性出现的重要组成部分是转录因子Stat3的激活。Stat3持续不适当的激活会导致靶基因表达，从而促进肿瘤细胞增殖，存活，侵袭和免疫抑制，它在对常规化学治疗剂和新型靶向化合物产生耐药性的过程中发挥了作用。由于这些原因，Stat3抑制被视为一种有前途的治疗策略。我们已经研究了酪氨酸激酶抑制剂canertinib对神经胶质瘤细胞Tu-2449的影响。在这些细胞中，Stat3在致癌驱动因子v-Src及其效应物胞质酪氨酸激酶Bmx的下游持续被磷酸化和激活。Tu-2449细胞的Canertinib暴露迅速引起Bmx激酶的抑制和Stat3的失活。细胞长时间暴露于canertinib会导致绝大多数细胞死亡。只有少数细胞对canertinib产生抗性，并在紧密的簇中存活。这些细胞已经变得耐药。当canertinib耐药细胞扩增并以较低的细胞密度培养时，它们恢复了对canertinib的敏感性。我们测量了Stat3激活程度与细胞密度的关系，发现更高的细胞密度伴随着Stat3激活的增加和Stat3目标基因的更高表达。我们建议通过紧密的细胞间相互作用（最有可能通过钙黏着蛋白的参与）诱导Stat3可以抵消canertinib对Bmx的抑制作用。细胞间的相互作用诱导了Stat3并补偿了canertinib对Stat3的抑制作用，从而瞬时保护了细胞免受抑制剂的细胞毒作用。我们测量了Stat3激活程度与细胞密度的关系，发现更高的细胞密度伴随着Stat3激活的增加和Stat3目标基因的更高表达。我们建议通过紧密的细胞间相互作用（最可能是通过钙黏着蛋白的参与）诱导Stat3可以抵消canertinib对Bmx产生的抑制作用。细胞间的相互作用诱导了Stat3并补偿了canertinib对Stat3的抑制作用，从而瞬时保护了细胞免受抑制剂的细胞毒作用。我们测量了Stat3激活程度与细胞密度的关系，发现更高的细胞密度伴随着Stat3激活的增加和Stat3目标基因的更高表达。我们建议通过紧密的细胞间相互作用（最可能是通过钙黏着蛋白的参与）诱导Stat3可以抵消canertinib对Bmx产生的抑制作用。细胞之间的相互作用诱导了Stat3并补偿了canertinib对Stat3的抑制作用，从而瞬时保护了细胞免受抑制剂的细胞毒作用。最有可能通过钙粘着蛋白的参与来抵消坎尼替尼对Bmx的抑制作用。细胞间的相互作用诱导了Stat3并补偿了canertinib对Stat3的抑制作用，从而瞬时保护了细胞免受抑制剂的细胞毒作用。最有可能通过钙粘着蛋白的参与来抵消坎尼替尼对Bmx的抑制作用。细胞间的相互作用诱导了Stat3并补偿了canertinib对Stat3的抑制作用，从而瞬时保护了细胞免受抑制剂的细胞毒作用。