Medical School, Ningbo University, Zhejiang 315211, PR China.
Mol Med Rep. 2012 Feb;5(2):503-8. doi: 10.3892/mmr.2011.682. Epub 2011 Nov 16.
Lung cancer is a malignant disease with poor outcome, which has led to a search for new therapeutics. The PI3K/Akt/mTOR and Ras/raf/Erk pathways are key regulators of tumor growth and survival. In the present study, their roles were evaluated by MTT assay, flow cytometry and Western blotting in lung cancer cells. We found that a high efficacy of antitumor activity was shown with GDC-0941 treatment in two gefitinib-resistant non-small cell lung cancer (NSCLC) cell lines, A549 and H460. In addition, H460 cells with activating mutations of PIK3CA were relatively more sensitive to GDC-0941 than A549 cells with wild-type PIK3CA. Furthermore, GDC-0941 was highly efficacious in combination with U0126 in inducing cell growth inhibition, G0-G1 arrest and cell apoptosis. These antitumor activities of combined treatment may be attributed to the alterations of G0-G1 phase regulators, apoptosis-related proteins and eukaryotic translation initiation factor 4B (eIF4B), induced by concomitant blockade of the PI3K/Akt/mTOR and Ras/raf/Erk pathways. In conclusion, this study suggests that multi‑targeted intervention is the most effective treatment for tumors. Additionally, the blockade of PI3K, mTOR and Erk with GDC-0941 and MEK inhibitors shows promise for treating gefitinib-resistant NSCLC.
肺癌是一种预后不良的恶性疾病，这促使人们寻找新的治疗方法。PI3K/Akt/mTOR 和 Ras/raf/Erk 通路是肿瘤生长和存活的关键调节因子。在本研究中，我们通过 MTT assay、流式细胞术和 Western blot 检测评估了这些通路在肺癌细胞中的作用。我们发现，GDC-0941 对两种吉非替尼耐药的非小细胞肺癌（NSCLC）细胞系 A549 和 H460 具有高效的抗肿瘤活性。此外，具有 PIK3CA 激活突变的 H460 细胞对 GDC-0941 相对比野生型 PIK3CA 的 A549 细胞更为敏感。此外，GDC-0941 与 U0126 联合使用在诱导细胞生长抑制、G0-G1 期阻滞和细胞凋亡方面具有高度疗效。这种联合治疗的抗肿瘤活性可能归因于同时阻断 PI3K/Akt/mTOR 和 Ras/raf/Erk 通路导致 G0-G1 期调节因子、凋亡相关蛋白和真核翻译起始因子 4B（eIF4B）的改变。总之，本研究表明多靶点干预是治疗肿瘤最有效的方法。此外，用 GDC-0941 和 MEK 抑制剂阻断 PI3K、mTOR 和 Erk 有望治疗吉非替尼耐药的 NSCLC。
