＂ALK＂(anaplastic lymphoma kinase)抑制劑在有＂ALK＂融合蛋白表現肺癌病人的治療

＂ALK＂ (anaplastic lymphoma kinase) Inhibitors in Lung Cancer Patients with ALK Fusion Protein

廖唯昱(Wei-Yu Liao) ； 施金元(Jin-Yuan Shi) ； 余忠仁(Chong-Jen Yu)

《台灣醫學》 18卷6期 (2014/11) Pp. 661-666

https://doi.org/10.6320/FJM.2014.18(6).06

摘要

有＂ALK＂(anaplastic lymphoma kinase)基因重組之肺癌在非小細胞肺癌佔的比例約4-8%，就像表皮生長因子受體(EGFR)突變一樣，＂ALK＂基因重組蛋白其有致癌驅動蛋白的特性造成癌細胞過度依賴此腫瘤蛋白，使得＂ALK＂抑制劑可非常有效的抑制＂ALK＂基因重組陽性細胞的生長。雖然第一代＂ALK＂抑制劑crizotinib臨床上治療＂ALK＂陽性非小細胞肺癌有顯著療效，但在接受一段時間的治療後會產生抗藥性。新一代的＂ALK＂抑制劑能有效對抗＂ALK＂基因突變與拷貝數增加造成的抗藥性，如ceritinib與alectinib等，在臨床上對於原生的＂ALK＂基因重組以及對crizotinib產生抗藥性的腫瘤都可以有抑制的效果。未來經由新的＂ALK＂抑制劑的研發與找尋可能的替代訊息傳遞途徑並給予適當治療，將能有效地延長病患的存活與改善生活品質。

關鍵字

非小細胞肺癌 ； ＂ALK＂基因重組 ； ＂ALK＂抑制劑

並列摘要

＂ALK＂ (anaplastic lymphoma kinase) rearrangements in non-small-cell lung cancer (NSCLC) have an estimated prevalence of 4-8%. ＂ALK＂ fusion proteins undergo ligand-independent dimerization and result in constitutive activation of the ＂ALK＂ tyrosine kinase. Tyrosine-kinase inhibitors that target the kinase activity of ＂ALK＂ have been found to have significant antiproliferative and proapoptotic effects. Although crizotinib treatment in ＂ALK＂ rearrangement-positive patients yields a pronounced clinical improvement, almost all patients eventually develop drug resistance. Ceritinib and alectinib are the new generation of ＂ALK＂ inhibitors, which overcome crizotinib resistance arising from ＂ALK＂ mutations or amplification. Other resistant mechanisms, such as activation of alternative pathways, remain to be discovered and validated. Further development of treatment strategy will improve the clinical outcome of patients with ＂ALK＂-positive advanced NSCLC.

並列關鍵字

non-small-cell lung cancer ； ＂ALK＂ rearrangements ； ＂ALK＂ inhibitors