Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at the University of California, Los Angeles, CA 90095, USA.
Cancer Discov. 2011 Nov;1(6):524-38. doi: 10.1158/2159-8290.CD-11-0124. Epub 2011 Sep 13.
Although it is known that mTOR complex 2 (mTORC2) functions upstream of Akt, the role of this protein kinase complex in cancer is not well understood. Through an integrated analysis of cell lines, in vivo models, and clinical samples, we demonstrate that mTORC2 is frequently activated in glioblastoma (GBM), the most common malignant primary brain tumor of adults. We show that the common activating epidermal growth factor receptor (EGFR) mutation (EGFRvIII) stimulates mTORC2 kinase activity, which is partially suppressed by PTEN. mTORC2 signaling promotes GBM growth and survival and activates NF-κB. Importantly, this mTORC2-NF-κB pathway renders GBM cells and tumors resistant to chemotherapy in a manner independent of Akt. These results highlight the critical role of mTORC2 in the pathogenesis of GBM, including through the activation of NF-κB downstream of mutant EGFR, leading to a previously unrecognized function in cancer chemotherapy resistance. These findings suggest that therapeutic strategies targeting mTORC2, alone or in combination with chemotherapy, will be effective in the treatment of cancer.
This study demonstrates that EGFRvIII-activated mTORC2 signaling promotes GBM proliferation, survival, and chemotherapy resistance through Akt-independent activation of NF-κB. These results highlight the role of mTORC2 as an integrator of two canonical signaling networks that are commonly altered in cancer, EGFR/phosphoinositide-3 kinase (PI3K) and NF-κB. These results also validate the importance of mTORC2 as a cancer target and provide new insights into its role in mediating chemotherapy resistance, suggesting new treatment strategies.
虽然已知 mTOR 复合物 2（mTORC2）在 Akt 上游发挥作用，但该蛋白激酶复合物在癌症中的作用尚未得到很好的理解。通过对细胞系、体内模型和临床样本的综合分析，我们证明 mTORC2 在胶质母细胞瘤（GBM）中经常被激活，GBM 是成人中最常见的恶性原发性脑肿瘤。我们表明，常见的激活表皮生长因子受体（EGFR）突变（EGFRvIII）刺激 mTORC2 激酶活性，而该活性部分受到 PTEN 的抑制。mTORC2 信号促进 GBM 的生长和存活，并激活 NF-κB。重要的是，这种 mTORC2-NF-κB 途径使 GBM 细胞和肿瘤对化疗产生耐药性，而与 Akt 无关。这些结果强调了 mTORC2 在 GBM 发病机制中的关键作用，包括通过激活突变 EGFR 下游的 NF-κB，导致在癌症化疗耐药性方面的先前未被认识的功能。这些发现表明，单独或联合化疗靶向 mTORC2 的治疗策略将对癌症的治疗有效。
本研究表明，EGFRvIII 激活的 mTORC2 信号通过 Akt 独立激活 NF-κB 促进 GBM 的增殖、存活和化疗耐药性。这些结果强调了 mTORC2 作为两个常见改变的经典信号网络的整合子的作用，即 EGFR/磷酸肌醇 3-激酶（PI3K）和 NF-κB。这些结果还验证了 mTORC2 作为癌症靶点的重要性，并提供了其在介导化疗耐药性中的作用的新见解，提示了新的治疗策略。
