Abstract
The discovery of an echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion gene led to improved clinical outcomes in patients with lung cancer after the development of the first ALK-targeting agent, crizotinib. Some second-generation ALK tyrosine kinase inhibitors (TKIs), which might be more potent than crizotinib or effective on crizotinib-resistant patients, have been developed. Although these ALK-TKIs show an excellent response initially, most patients eventually acquire resistance. Therefore, careful consideration of the resistance mechanisms might lead to superior therapeutic strategies. Here, we summarize the history of ALK-TKIs and their underlying resistance mechanisms in both the preclinical and clinical settings. In addition, we discuss potential future treatment strategies in ALK-TKI-naïve and -resistant patients with lung cancer harboring the EML4-ALK fusion gene.
Highlights
Several gene aberrations are known to cause different types of cancer
The first important breakthrough was the development of imatinib, a BCR-ABL tyrosine kinase inhibitor (TKI), for chronic myeloid leukemia (CML) patients harboring the Philadelphia chromosome, which results from a translocation between chromosomes 9 and 22
Maemondo et al reported that treatment with gefitinib achieved a longer median progression-free survival (PFS) of 10.8 months and a higher response rate of 73.7% compared with standard chemotherapy in non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations [5]
Summary
Several gene aberrations are known to cause different types of cancer. This knowledge has led to the development of molecular-targeted drugs, and cancer treatment has progressed impressively over the Cancers 2015, 7 past decade. The first important breakthrough was the development of imatinib, a BCR-ABL tyrosine kinase inhibitor (TKI), for chronic myeloid leukemia (CML) patients harboring the Philadelphia chromosome, which results from a translocation between chromosomes 9 and 22 This drug achieved long-term complete remission, which has excited physicians around the world. In addition to the EML4-ALK fusion gene in lung cancer, various ALK-related diseases have been reported, including familial neuroblastoma [10], renal cell carcinomas [11,12,13,14], esophageal squamous cell carcinomas [15,16], breast cancer, colonic adenocarcinomas [17], glioblastoma multiforme [18,19], and anaplastic thyroid cancer [20] These tumors were sensitive to ALK-TKIs [21,22]. We summarize future therapeutic strategies for ALK-positive lung cancer patients
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