Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Mol Cancer Ther. 2011 Dec;10(12):2437-48. doi: 10.1158/1535-7163.MCT-11-0235. Epub 2011 Oct 6.
Recent reports have shown limited anticancer therapeutic efficacy of insulin-like growth factor receptor (IGF-1R)-targeted monoclonal antibodies (mAb), but the resistance mechanisms have not been completely identified. Because cooperation between epidermal growth factor receptor (EGFR) and IGF-IR could cause resistance to inhibitors of individual receptor tyrosine kinases, we investigated the involvement of EGFR signaling in resistance to IGF-1R mAb and the underlying mechanisms of action. Most head and neck squamous cell carcinoma (HNSCC) tissues had coexpression of total and phosphorylated IGF-1R and EGFR at high levels compared with paired adjacent normal tissues. Treatment with cixutumumab (IMC-A12), a fully humanized IgG1 mAb, induced activation of Akt and mTOR, resulting in de novo synthesis of EGFR, Akt1, and survivin proteins and activation of the EGFR pathway in cixutumumab-resistant HNSCC and non-small cell lung cancer (NSCLC) cells. Targeting mTOR and EGFR pathways by treatment with rapamycin and cetuximab (an anti-EGFR mAb), respectively, prevented cixutumumab-induced expression of EGFR, Akt, and survivin and induced synergistic antitumor effects in vitro and in vivo. These data show that resistance to IGF-1R inhibition by mAbs is associated with Akt/mTOR-directed enhanced synthesis of EGFR, Akt1, and survivin. Our findings suggest that Akt/mTOR might be effective targets to overcome the resistance to IGF-1R mAbs in HNSCC and NSCLC.
最近的报告表明，胰岛素样生长因子受体（IGF-1R）靶向单克隆抗体（mAb）的抗癌治疗效果有限，但耐药机制尚未完全确定。由于表皮生长因子受体（EGFR）和 IGF-IR 之间的合作可能导致对个体受体酪氨酸激酶抑制剂的耐药性，我们研究了 EGFR 信号在 IGF-1R mAb 耐药中的参与以及作用的潜在机制。与配对的相邻正常组织相比，大多数头颈部鳞状细胞癌（HNSCC）组织中总 IGF-1R 和磷酸化 IGF-1R 以及 EGFR 的表达均较高。用 Cixutumumab（IMC-A12）治疗，一种完全人源化 IgG1 mAb，诱导 Akt 和 mTOR 的激活，导致 EGFR、Akt1 和 survivin 蛋白的从头合成，并激活 Cixutumumab 耐药的 HNSCC 和非小细胞肺癌（NSCLC）细胞中的 EGFR 途径。用雷帕霉素和 Cetuximab（一种抗 EGFR mAb）分别靶向 mTOR 和 EGFR 途径，可防止 Cixutumumab 诱导的 EGFR、Akt 和 survivin 的表达，并在体外和体内诱导协同的抗肿瘤作用。这些数据表明，mAb 对 IGF-1R 抑制的耐药性与 Akt/mTOR 定向增强的 EGFR、Akt1 和 survivin 的合成有关。我们的研究结果表明，Akt/mTOR 可能是克服 HNSCC 和 NSCLC 中 IGF-1R mAb 耐药性的有效靶点。
