Department of Pharmacology and Systems Therapeutics, Systems Biology Center New York, Mount Sinai School of Medicine, New York, NY, USA.
J Pharmacol Exp Ther. 2012 Nov;343(2):509-19. doi: 10.1124/jpet.112.196097. Epub 2012 Aug 6.
Acquired drug resistance represents a major obstacle to using sunitinib for the treatment of solid tumors. Here, we examined the cellular and molecular alterations in tumors that are associated with acquired brain tumor resistance to sunitinib by using an in vivo model. U87MG tumors obtained from nude mice that received sunitinib (40 mg/kg/day) for 30 days were classified into sunitinib-sensitive and -resistant groups based on tumor volume and underwent targeted gene microarray and protein array analyses. The expression of several angiogenesis-associated genes was significantly modulated in sunitinib-treated tumors compared with those in control tumors (p<0.05), whereas no significant differences were observed between sunitinib-sensitive and -resistant tumors (p>0.05). Tumor vasculature based on microvessel density, neurogenin 2 chondroitin sulfate proteoglycan density, and α-smooth muscle actin density was also similar in sunitinib-treatment groups (p>0.05). The moderate increase in unbound sunitinib tumor-to-plasma area-under-the-curve ratio in sunitinib-resistant mice was accompanied by up-regulated ATP-binding cassette G2 expression in tumor. The most profound difference between the sunitinib-sensitive and -resistant groups was found in the expression of several phosphorylated proteins involved in intracellular signaling. In particular, phospholipase C-γ1 phosphorylation in sunitinib-resistant tumors was up-regulated by 2.6-fold compared with that in sunitinib-sensitive tumors (p<0.05). In conclusion, acquired sunitinib resistance in U87MG tumors is not associated with revascularization in tumors, but rather with the activation of alternate prosurvival pathways involved in an escape mechanism facilitating tumor growth and possibly insufficient drug uptake in tumor cells caused by an up-regulated membrane efflux transporter.
获得性药物耐药性是使用舒尼替尼治疗实体瘤的主要障碍。在这里，我们通过体内模型研究了与脑肿瘤对舒尼替尼获得性耐药相关的肿瘤细胞和分子变化。根据肿瘤体积，将从接受舒尼替尼（40mg/kg/天）治疗 30 天的裸鼠中获得的 U87MG 肿瘤分为舒尼替尼敏感和耐药组，并进行了靶向基因微阵列和蛋白质阵列分析。与对照肿瘤相比，舒尼替尼处理的肿瘤中几种血管生成相关基因的表达明显受到调节（p<0.05），而舒尼替尼敏感和耐药肿瘤之间没有观察到显著差异（p>0.05）。基于微血管密度、神经基因 2 硫酸软骨素蛋白聚糖密度和α-平滑肌肌动蛋白密度的肿瘤血管生成也在舒尼替尼治疗组中相似（p>0.05）。在舒尼替尼耐药小鼠中，未结合的舒尼替尼肿瘤-血浆 AUC 比值的适度增加伴随着肿瘤中 ABCG2 表达的上调。舒尼替尼敏感和耐药组之间最显著的差异是参与细胞内信号转导的几种磷酸化蛋白的表达。特别是，舒尼替尼耐药肿瘤中 PLC-γ1 的磷酸化水平比舒尼替尼敏感肿瘤高 2.6 倍（p<0.05）。总之，U87MG 肿瘤中获得性舒尼替尼耐药与肿瘤内再血管化无关，而是与参与逃避机制的替代生存途径的激活有关，该逃避机制促进肿瘤生长，并且可能由于膜外排转运体的上调导致肿瘤细胞中药物摄取不足。
