Ludwig Center at Dana-Farber/Harvard and Center for Sarcoma and Bone Oncology, Department of Medical Oncology, Harvard Medical School, Boston, Massachusetts 02215, USA.
Clin Cancer Res. 2013 Jul 15;19(14):3796-807. doi: 10.1158/1078-0432.CCR-12-3647. Epub 2013 May 28.
Chondrosarcomas are notoriously resistant to cytotoxic chemotherapeutic agents. We sought to identify critical signaling pathways that contribute to their survival and proliferation, and which may provide potential targets for rational therapeutic interventions.
Activation of receptor tyrosine kinases (RTK) was surveyed using phospho-RTK arrays. S6 phosphorylation and NRAS mutational status were examined in chondrosarcoma primary tumor tissues. siRNA or small-molecule inhibitors against RTKs or downstream signaling proteins were applied to chondrosarcoma cells and changes in biochemical signaling, cell cycle, and cell viability were determined. In vivo antitumor activity of BEZ235, a phosphoinositide 3-kinase (PI3K)/mTOR inhibitor, was evaluated in a chondrosarcoma xenograft model.
Several RTKs were identified as critical mediators of cell growth, but the RTK dependencies varied among cell lines. In exploration of downstream signaling pathways, strong S6 phosphorylation was found in 69% of conventional chondrosarcomas and 44% of dedifferentiated chondrosarcomas. Treatment with BEZ235 resulted in dramatic reduction in the growth of all chondrosarcoma cell lines. Tumor growth was similarly inhibited in a xenograft model of chondrosarcoma. In addition, chondrosarcoma cells with an NRAS mutation were sensitive to treatment with a mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) inhibitor. Functional NRAS mutations were found in 12% of conventional central chondrosarcomas.
RTKs are commonly activated in chondrosarcoma, but because of their considerable heterogeneity, targeted inhibition of the PI3K/mTOR pathway represents a rational therapeutic strategy. Chondrosarcomas with NRAS mutations may benefit from treatment with MEK inhibitors.
软骨肉瘤对细胞毒性化疗药物具有明显的耐药性。我们试图确定导致其存活和增殖的关键信号通路，这些通路可能为合理的治疗干预提供潜在的靶点。
使用磷酸化受体酪氨酸激酶（RTK）阵列调查 RTK 的激活情况。在软骨肉瘤原发肿瘤组织中检查 S6 磷酸化和 NRAS 突变状态。将针对 RTK 或下游信号蛋白的 siRNA 或小分子抑制剂应用于软骨肉瘤细胞，并确定生化信号、细胞周期和细胞活力的变化。在软骨肉瘤异种移植模型中评估了磷脂酰肌醇 3-激酶（PI3K）/哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂 BEZ235 的体内抗肿瘤活性。
鉴定出几种 RTK 是细胞生长的关键介质，但 RTK 的依赖性在细胞系之间有所不同。在探索下游信号通路时，发现 69%的传统软骨肉瘤和 44%的去分化软骨肉瘤中 S6 磷酸化强烈。BEZ235 的治疗导致所有软骨肉瘤细胞系的生长明显减少。在软骨肉瘤的异种移植模型中，肿瘤生长也受到抑制。此外，具有 NRAS 突变的软骨肉瘤细胞对丝裂原活化蛋白激酶/细胞外信号调节激酶激酶（MEK）抑制剂的治疗敏感。在 12%的传统中央软骨肉瘤中发现了功能性 NRAS 突变。
RTK 在软骨肉瘤中普遍激活，但由于其异质性很大，靶向抑制 PI3K/mTOR 通路代表了一种合理的治疗策略。具有 NRAS 突变的软骨肉瘤可能受益于 MEK 抑制剂治疗。
