PDF(Pubmed)
Abstract：
Therapy failure with the tyrosine kinase inhibitor (TKI) sunitinib remains a great challenge in metastatic renal cell carcinoma (mRCC). Growing evidence indicates that the tumour subpopulation can enter a transient, non-mutagenic drug-tolerant state to endure the treatment underlying the minimal residual disease and tumour relapse. Drug tolerance to sunitinib remains largely unexplored in RCC. Here, we show that sunitinib-tolerant 786-O/S and Caki-2/S cells are induced by prolonged drug treatment showing reduced drug sensitivity, enhanced clonogenicity, and DNA synthesis. Sunitinib-tolerance developed via dynamic processes, including (i) engagement of c-MET and AXL pathways, (ii) alteration of stress-induced p38 kinase and pro-survival BCL-2 signalling, (iii) extensive actin remodelling, which was correlated with activation of focal adhesion proteins. Remarkably, the acute drug response in both sensitive and sunitinib-tolerant cell lines led to dramatic fine-tuning of the actin-cytoskeleton and boosted cellular migration and invasion, indicating that the drug-response might depend on cell state transition rather than pre-existing mutations. The drug-tolerant state was transiently acquired, as the cells resumed initial drug sensitivity after >10 passages under drug withdrawal, reinforcing the concept of dynamic regulation and phenotypic heterogeneity. Our study described molecular events contributing to the reversible switch into sunitinib-tolerance, providing possible novel therapeutic opportunities in RCC.
摘要：
酪氨酸激酶抑制剂（TKI）舒尼替尼的治疗失败仍然是转移性肾细胞癌（mRCC）的巨大挑战。越来越多的证据表明，肿瘤亚群可以进入一个短暂的，非诱变的药物耐受状态，以承受微小残留疾病和肿瘤复发的治疗。在RCC中，对舒尼替尼的药物耐受性仍未被探索。这里,我们表明舒尼替尼耐受786-O/S和Caki-2/S细胞是由长时间的药物治疗诱导的，显示药物敏感性降低，增强克隆性，和DNA合成。通过动态过程开发的舒尼替尼耐受性，包括(I)参与c-MET和AXL途径，（ii）应激诱导的p38激酶和促生存BCL-2信号的改变，(iii)广泛的肌动蛋白重塑，这与粘着斑蛋白的激活有关。值得注意的是,敏感和舒尼替尼耐受细胞系中的急性药物反应导致肌动蛋白细胞骨架的显着微调，并增强细胞迁移和侵袭，表明药物反应可能取决于细胞状态转变，而不是预先存在的突变。药物耐受状态是短暂获得的，当细胞在停药>10次传代后恢复初始药物敏感性时，强化动态调控和表型异质性的概念。我们的研究描述了有助于可逆转换为舒尼替尼耐受的分子事件，为RCC提供可能的新治疗机会。
