Division of Medical Oncology, S. G. Moscati Hospital, Avellino, Italy.
Curr Pharm Des. 2013;19(30):5333-43. doi: 10.2174/13816128113199990343.
Lung cancer is the leading cause of mortality world-wide. Non Small Cell Lung Cancer (NSCLC) is a particularly aggressive cancer, the optimum management of which is still being determined. In the next years modest survival improvement can be expected by chemotherapy. Advances in understanding of the molecular pathogenesis of lung cancer have led to the identification of several specific targets for therapeutic agents. Targeting the epidermal growth factor receptor (EGFR) has played a central role in advancing NSCLC research, treatment, and patient outcome over the last several years. In lung cancer, 10-15% of NSCLC contain activating mutations in the EGFR kinase conferring hypersensitivity to the oral TKIs gefitinib and erlotinib, have been demonstrated to be important predictive factors when selecting patients to be treated with these two agents. More recently, another molecular abnormality, the translocation of the anaplastic lymphoma kinase (ALK) gene that drives NSCLC in a different group of patients has been found in 4 to 5% of NSCLC. The rearrangement results in an EML4 - AKL fusion gene, which increases ALK activity. Inhibitors of ALK kinase have been developed and investigated. Crizotinib, an orally ALK and met proto-oncogene (MET) inhibitor, was very well tolerated and produced dramatic antitumor activity in early-stage trials which facilitated a faster than normal move into late-stage trials for EML4-ALK -positive NSCLC patients treatment. In a phase III randomized that showed progression free survival benefit as compared to chemotherapy in second-line setting. Several novel selective inhibitors of ALK kinase are currently in preclinical or early clinical testing. Since the discovery that Met pathway is one of the most frequently dysregulated pathways in human cancer, Met inhibitors, with varying kinase selectivity profiles ranging from highly selective to multi-targeted have been studied in the clinic and good progress has been achieved. A number of studies suggest that the PI3K/Akt signaling pathway is central to NSCLC growth and survival. Given the importance of activated PI3K signaling in cancer, several PI3K inhibitors are currently one of the most recent drug targets in oncology, with several small molecules in early stages of clinical development. This review will focus on the role of EGFR, ALK, MET, and PI3K inhibitors in the treatment of NSCLC.
肺癌是全球范围内导致死亡的主要原因。非小细胞肺癌（NSCLC）是一种特别侵袭性的癌症，其最佳治疗方法仍在确定中。在未来几年，通过化疗可以预期适度的生存改善。对肺癌分子发病机制的深入理解导致了针对几种治疗药物的特定靶点的鉴定。针对表皮生长因子受体（EGFR）在过去几年中在推进 NSCLC 研究、治疗和患者预后方面发挥了核心作用。在肺癌中，10-15%的 NSCLC 中存在 EGFR 激酶的激活突变，使患者对口服 TKIs 吉非替尼和厄洛替尼敏感，已被证明是选择这些药物治疗患者的重要预测因素。最近，另一种分子异常，即间变性淋巴瘤激酶（ALK）基因的易位，在不同组的 NSCLC 患者中发现了 4-5%的 NSCLC。这种重排导致 EML4-ALK 融合基因的产生，从而增加了 ALK 的活性。已经开发并研究了针对 ALK 激酶的抑制剂。克唑替尼，一种口服的 ALK 和间质原癌基因（MET）抑制剂，在早期试验中具有良好的耐受性，并产生了显著的抗肿瘤活性，这使得 EML4-ALK 阳性 NSCLC 患者的治疗更快地进入晚期试验。在一项 III 期随机试验中，与二线化疗相比，无进展生存期有获益。目前有几种新型选择性 ALK 激酶抑制剂正在进行临床前或早期临床试验。自从发现 Met 通路是人类癌症中最常失调的通路之一以来，Met 抑制剂，其激酶选择性谱从高度选择性到多靶点不等，已在临床上进行了研究，并取得了良好的进展。多项研究表明，PI3K/Akt 信号通路是 NSCLC 生长和存活的关键。鉴于激活的 PI3K 信号在癌症中的重要性，几种 PI3K 抑制剂是目前肿瘤学中最新的药物靶点之一，有几种小分子处于临床开发的早期阶段。这篇综述将重点介绍 EGFR、ALK、MET 和 PI3K 抑制剂在 NSCLC 治疗中的作用。
