Department of Oncology, Molecular Therapeutics Program, Karmanos Cancer Institute, Detroit, MI, USA.
Clin Lung Cancer. 2013 Jul;14(4):322-32. doi: 10.1016/j.cllc.2012.12.001. Epub 2013 Jan 16.
Mutations in the epidermal growth factor receptor gene (EGFR) are frequently observed in non-small-cell lung cancer (NSCLC), occurring in about 40% to 60% of never-smokers and in about 17% of patients with adenocarcinomas. EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, have transformed therapy for patients with EGFR-mutant NSCLC and have proved superior to chemotherapy as first-line treatment for this patient group. Despite these benefits, there are currently 2 key challenges associated with EGFR inhibitor therapy for patients with NSCLC. First, only 85% to 90% of patients with the EGFR mutation derive clinical benefit from EGFR TKIs, with the remainder demonstrating innate resistance to therapy. Second, acquired resistance to EGFR TKIs inevitably occurs in patients who initially respond to therapy, with a median duration of response of about 10 months. Mutant EGFR activates various subcellular signaling cascades, including the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway, which demonstrates maintained activity in a variety of TKI-resistant cancers. Given the fundamental role of the PI3K/Akt/mTOR pathway in tumor oncogenesis, proliferation, and survival, PI3K pathway inhibitors have emerged as a possible solution to the problem of EGFR TKI resistance. However resistance to EGFR TKIs is associated with considerable heterogeneity and complexity. Preclinical experiments investigating these phenomena suggest that in some patients, PI3K inhibitors will have to be paired with other targeted agents if they are to be effective. This review discusses the preclinical data supporting PI3K/Akt/mTOR pathway inhibitor combinations in EGFR TKI-resistant NSCLC from the perspective of the various agents currently being investigated in clinical trials.
表皮生长因子受体基因（EGFR）的突变在非小细胞肺癌（NSCLC）中经常被观察到，在从不吸烟者中约占 40%至 60%，在腺癌患者中约占 17%。表皮生长因子受体酪氨酸激酶抑制剂（TKI），如吉非替尼和厄洛替尼，已经改变了 EGFR 突变型 NSCLC 患者的治疗方法，并且已经证明比化疗作为该患者群体的一线治疗更有效。尽管有这些益处，但目前 EGFR 抑制剂治疗 NSCLC 患者存在 2 个关键挑战。首先，只有 85%至 90%的 EGFR 突变患者从 EGFR TKI 中获得临床益处，其余患者对治疗具有先天耐药性。其次，对 EGFR TKI 的获得性耐药性不可避免地会发生在最初对治疗有反应的患者中，中位反应持续时间约为 10 个月。突变型 EGFR 激活各种细胞内信号级联反应，包括磷脂酰肌醇 3-激酶（PI3K）/Akt/哺乳动物雷帕霉素靶蛋白（mTOR）通路，该通路在各种 TKI 耐药性癌症中保持活性。鉴于 PI3K/Akt/mTOR 通路在肿瘤发生、增殖和存活中的基本作用，PI3K 通路抑制剂已成为解决 EGFR TKI 耐药问题的一种可能方法。然而，对 EGFR TKI 的耐药性与相当大的异质性和复杂性有关。这些现象的临床前实验表明，在一些患者中，如果要有效，PI3K 抑制剂将不得不与其他靶向药物联合使用。这篇综述从目前正在临床试验中研究的各种药物的角度讨论了支持 PI3K/Akt/mTOR 通路抑制剂联合用于 EGFR TKI 耐药 NSCLC 的临床前数据。
