Targeted therapies in development for non-small cell lung cancer.
Targeted therapies in development for non-small cell lung cancer.
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DOI：
10.4103/1477-3163.123972
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发表时间：
2013
影响因子：
--
通讯作者：
Dy GK
中科院分区：
文献类型：
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作者：
Reungwetwattana T;Dy GK
在过去的几十年里，在各种恶性肿瘤中反复发现了一些异常的肿瘤发生过程和信号转导途径是由“可药物化”的蛋白激酶介导的，这导致了药物开发的革命性变化。在非小细胞肺癌（NSCLC）中，ErbB受体家族(如表皮生长因子受体EGFR、HER2（人表皮生长因子受体2）、RAS（大鼠肉瘤基因）、BRAF （v-raf鼠肉瘤病毒癌基因同源物B1）、MAPK（丝裂原活化蛋白激酶）c-MET （c-间质上皮转化）、FGFR（成纤维细胞生长因子受体）、DDR2 （diskidin结构域受体2）、PIK3CA（磷脂酰肌醇-4,5-二磷酸- 3激酶，催化亚基α）、PTEN（磷酸酶和紧张素同源物）、AKT（蛋白激酶B）、ALK（间变性淋巴瘤激酶）、RET（转染时重排）、ROS1（活性氧物种1）和EPH（促红细胞生成素产生肝癌）是目前临床开发的各种药物的关键靶点。这些致癌靶点通过多种互传途径发挥其选择性生长优势，如RAS/RAF/MEK、磷酸肌苷3-激酶/AKT/哺乳动物雷帕霉素靶点和src信号转导和转录信号。最近的临床研究表明，EGFR酪氨酸激酶抑制剂和克唑替尼被认为是转移性NSCLC中非常有效的靶向治疗方法。目前，有5种分子靶向药物被批准用于晚期NSCLC的治疗：用于EGFR阳性突变的吉非替尼、厄洛替尼和阿法替尼，用于表皮微管相关蛋白样4 (EML4)-ALK易位阳性的克里唑替尼和贝伐单抗。此外，致癌突变蛋白受蛋白质运输途径的调控，特别是通过热休克蛋白90系统。与单一治疗方法相比，预测并证明影响这些信号传导和细胞内过程中各个节点的药物组合在克服治疗耐药方面具有协同作用和优势。了解肿瘤微环境在恶性表型发展和维持中的作用也提供了额外的治疗方法。最近，肿瘤免疫学知识的提高为有希望的非小细胞肺癌免疫治疗奠定了基础。本文将重点介绍NSCLC靶向治疗发展的基本原理，以及用于预防或克服不可避免的治疗耐药的各种策略。
The iterative discovery in various malignancies during the past decades that a number of aberrant tumorigenic processes and signal transduction pathways are mediated by “druggable” protein kinases has led to a revolutionary change in drug development. In non-small cell lung cancer (NSCLC), the ErbB family of receptors (e.g., EGFR [epidermal growth factor receptor], HER2 [human epidermal growth factor receptor 2]), RAS (rat sarcoma gene), BRAF (v-raf murine sarcoma viral oncogene homolog B1), MAPK (mitogen-activated protein kinase) c-MET (c-mesenchymal-epithelial transition), FGFR (fibroblast growth factor receptor), DDR2 (discoidin domain receptor 2), PIK3CA (phosphatidylinositol-4,5-bisphosphate3-kinase, catalytic subunit alpha)), PTEN (phosphatase and tensin homolog), AKT (protein kinase B), ALK (anaplastic lym phoma kinase), RET (rearranged during transfection), ROS1 (reactive oxygen species 1) and EPH (erythropoietin-producing hepatoma) are key targets of various agents currently in clinical development. These oncogenic targets exert their selective growth advantage through various intercommunicating pathways, such as through RAS/RAF/MEK, phosphoinositide 3-kinase/AKT/mammalian target of rapamycin and SRC-signal transduction and transcription signaling. The recent clinical studies, EGFR tyrosine kinase inhibitors and crizotinib were considered as strongly effective targeted therapies in metastatic NSCLC. Currently, five molecular targeted agents were approved for treatment of advanced NSCLC: Gefitinib, erlotinib and afatinib for positive EGFR mutation, crizotinib for positive echinoderm microtubule-associated protein-like 4 (EML4)-ALK translocation and bevacizumab. Moreover, oncogenic mutant proteins are subject to regulation by protein trafficking pathways, specifically through the heat shock protein 90 system. Drug combinations affecting various nodes in these signaling and intracellular processes are predicted and demonstrated to be synergistic and advantageous in overcoming treatment resistance compared with monotherapy approaches. Understanding the role of the tumor microenvironment in the development and maintenance of the malignant phenotype provided additional therapeutic approaches as well. More recently, improved knowledge on tumor immunology has set the stage for promising immunotherapies in NSCLC. This review will focus on the rationale for the development of targeted therapies in NSCLC and the various strategies employed in preventing or overcoming the inevitable occurrence of treatment resistance.