Thoracic Oncology Center, Massachusetts General Hospital Cancer Center, Boston, Massachusetts 02114, USA.
Clin Cancer Res. 2011 Apr 15;17(8):2081-6. doi: 10.1158/1078-0432.CCR-10-1591. Epub 2011 Feb 2.
Several decades of cancer research have revealed a pivotal role for tyrosine kinases as key regulators of signaling pathways, controlling cell growth and differentiation. Deregulation of tyrosine kinase-mediated signaling occurs frequently in cancer and is believed to drive the initiation and progression of disease. Chromosomal rearrangements involving the tyrosine kinase anaplastic lymphoma kinase (ALK) occur in a variety of human malignancies including non-small cell lung cancer (NSCLC), anaplastic large cell lymphomas, and inflammatory myofibroblastic tumors. The aberrant activation of ALK signaling leads to "oncogene addiction" and marked sensitivity to ALK inhibitors such as crizotinib (PF-02341066). This review focuses on ALK rearrangements in NSCLC, starting with the discovery of the EML4-ALK fusion oncogene, and culminating in the recent validation of ALK as a therapeutic target in patients with ALK-rearranged NSCLC. Current efforts seek to expand the role of ALK kinase inhibition in lung and other cancers and to address the molecular basis for the development of resistance.
几十年来的癌症研究揭示了酪氨酸激酶作为信号通路关键调节剂的关键作用，控制着细胞的生长和分化。酪氨酸激酶介导的信号转导失调在癌症中经常发生，被认为是驱动疾病的发生和进展的原因。涉及酪氨酸激酶间变性淋巴瘤激酶（ALK）的染色体重排发生在多种人类恶性肿瘤中，包括非小细胞肺癌（NSCLC）、间变大细胞淋巴瘤和炎性肌纤维母细胞瘤。ALK 信号的异常激活导致“癌基因成瘾”，并对 ALK 抑制剂（如克唑替尼[PF-02341066]）具有显著的敏感性。这篇综述重点介绍了 NSCLC 中的 ALK 重排，从 EML4-ALK 融合致癌基因的发现开始，最终最近验证了 ALK 作为 ALK 重排 NSCLC 患者的治疗靶点。目前的努力旨在扩大 ALK 激酶抑制在肺癌和其他癌症中的作用，并解决耐药性的分子基础。
