- 期刊
Anaplastic Lymphoma Kinase (ALK) Inhibitors: New Cancer Breakthroughs for Lung Cancer
間變性淋巴瘤激酶（ALK）抑制劑：肺癌新突破
摘要
自從十年前第一個抗癌激酶抑制劑-基利克上市以來，美國食品與藥物管理局一共核准了12個小分子激酶抑制劑上市作為抗癌藥物。由於激酶過度表現活性與癌細胞增生、轉移以及突變等息息相關，故激酶抑制劑已成為癌症治療中相當重要的一個方法。2007年，首次文獻報導在非小細胞肺癌（NSCLC）病患中，發現了一個新型的轉位基因突變，以及其轉譯之融合蛋白。此轉位基因隨後鑑定為間變性淋巴瘤激酶（ALK）基因以及棘皮動物微管結合蛋白4（EML4）基因轉位組合而來。由於文獻已有報導間變性淋巴瘤激酶的異常表現與異生性大細胞淋巴瘤（ALCL）、神經母細胞瘤以及非小細胞肺線癌有很強的關聯性，故有許多的研究發展ALK 抑制劑成為新穎抗癌藥物。在本篇回顧中，我們整理了目前發展中的ALK 抑制劑，特別是最近剛通過美國食品與藥物管理局快速審核，核准用以治療NSCLC的crizotinib做一介紹。此外，由於目前已有發現對於crizotinib具有抗藥性的突變（ALK（上標 L1196M）與ALK（上標 C1156Y））產生，因此我們也針對新一代活性更強，對突變ALK有效的第二代抑制劑，例如AP-26113、X-396與CH5424802等等藥物做更詳細之介紹。總結，自愛瑞莎與得舒緩核准上市以來，對NSCLC的治療開啟了一個「個人化治療」的新紀元，而新一代的抗癌藥物crizotinib，只花了六年的時間便通過審核並核准上市，這樣的突破性發展，更將「個人化治療」帶入一個嶄新的境界。相信在不久的將來，由於「個人化治療」的蓬勃發展，將會有更多的小分子ALK抑制劑可以上市。
並列摘要
Kinases have become clinically validated targets for cancer therapy since imatinib first launched ten years ago. Twelve small molecule kinase-targeting agents have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of cancer. It indicates that deregulation of protein kinase, for example by amplification, translocation or mutation, is considered as a promising strategy for targeted cancer treatment. Thus, drugs targeting abnormal kinase activity hold great promise as potential targeted treatments. A new translocation gene mutation in non-small-cell lung cancer (NSCLC) was recently discovered in 2007: an unusual protein encoded from a fusion gene of anaplastic lymphoma kinase (ALK) and echinoderm microtubule-associated protein-like 4 (EML-4). Due to the connection between the aberrant expression and activation of ALK with the onset and progression of ALK-related ALCL, neuroblastomas and NSCLC, several agents have been developed to target oncogenic ALK kinase for the treatment of cancer. This manuscript provides a comprehensive review of ALK inhibitors in clinical development, in particular crizotinib, which received FDA's accelerated approval for the treatment of NSCLC patients. Due to several point mutations, ALK(superscript L1196M) and ALK(superscript C1156Y), acquired crizotinib resistance, a number of second-generation ALK inhibitors against both wild-type and mutated resistant ALK, such as AP-26113, X-396 and CH5424802, will be also discussed. In summary, approval of gefitinib and erlotinib for the treatment of NSCLC patients opens up new door for personalized therapy. Thus the breakthrough success of crizotinib against EML4-ALK-positive NSCLC cancers takes only six years from bench to bedside and marks a new era of personalized therapy. It is believed that one or more small-molecule ALK inhibitors are expected to reach the market in the very near future.