Echeverry N, Ziltener G, Barbone D, Weder W, Stahel R A, Broaddus V C, Felley-Bosco E
Laboratory of Molecular Oncology, Clinic of Oncology, University Hospital of Zürich, Häldeliweg 4, Zürich 8044, Switzerland.
Department of Medicine, Division of Pulmonary, San Francisco General Hospital, University of California San Francisco, San Francisco, CA 94110, USA.
Cell Death Dis. 2015 May 7;6(5):e1757. doi: 10.1038/cddis.2015.124.
Malignant pleural mesothelioma (MPM) originates in most of the cases from chronic inflammation of the mesothelium due to exposure to asbestos fibers. Given the limited effect of chemotherapy, a big effort is being made to find new treatment options. The PI3K/mTOR pathway was reported to be upregulated in MPM. We tested the cell growth inhibition properties of two dual PI3K/mTOR inhibitors NVP-BEZ235 and GDC-0980 on 19 MPM cell lines. We could identify resistant and sensitive lines; however, there was no correlation to the downregulation of PI3K/mTOR activity markers. As a result of mTOR inhibition, both drugs efficiently induced long-term autophagy but not cell death. Autophagy blockade by chloroquine in combination with the dual PI3K/mTOR inhibitors significantly induced caspase-independent cell death involving RIP1 in the sensitive cell line SPC212. Cell death in the resistant cell line Mero-82 was less pronounced, and it was not induced via RIP1-dependent mechanism, suggesting the involvement of RIP1 downstream effectors. Cell death induction was confirmed in 3D systems. Based on these results, we identify autophagy as one of the main mechanisms of cell death resistance against dual PI3K/mTOR inhibitors in MPM. As PI3K/mTOR inhibitors are under investigation in clinical trials, these results may help interpreting their outcome and suggest ways for intervention.
恶性胸膜间皮瘤（MPM）在大多数情况下起源于因接触石棉纤维导致的间皮慢性炎症。鉴于化疗效果有限，人们正在大力寻找新的治疗方案。据报道，PI3K/mTOR通路在MPM中上调。我们测试了两种双重PI3K/mTOR抑制剂NVP-BEZ235和GDC-0980对19种MPM细胞系的细胞生长抑制特性。我们能够识别出耐药和敏感细胞系；然而，这与PI3K/mTOR活性标志物的下调并无关联。作为mTOR抑制的结果，两种药物均有效诱导长期自噬，但未诱导细胞死亡。在敏感细胞系SPC212中，氯喹联合双重PI3K/mTOR抑制剂阻断自噬显著诱导了涉及RIP1的非半胱天冬酶依赖性细胞死亡。耐药细胞系Mero-82中的细胞死亡不太明显，且不是通过RIP1依赖性机制诱导的，这表明RIP1下游效应器参与其中。在三维系统中证实了细胞死亡诱导。基于这些结果，我们确定自噬是MPM中细胞对双重PI3K/mTOR抑制剂产生死亡抗性的主要机制之一。由于PI3K/mTOR抑制剂正在进行临床试验研究，这些结果可能有助于解释其结果并提出干预方法。
