Abstract
Anaplastic lymphoma kinase (ALK) is a validated molecular target in several ALK-rearranged malignancies, particularly in non-small-cell lung cancer (NSCLC), which has generated considerable interest and effort in developing ALK tyrosine kinase inhibitors (TKI). Crizotinib was the first ALK inhibitor to receive FDA approval for ALK-positive NSCLC patients treatment. However, the clinical benefit observed in targeting ALK in NSCLC is almost universally limited by the emergence of drug resistance with a median of occurrence of approximately 10 months after the initiation of therapy. Thus, to overcome crizotinib resistance, second/third-generation ALK inhibitors have been developed and received, or are close to receiving, FDA approval. However, even when treated with these new inhibitors tumors became resistant, both in vitro and in clinical settings. The elucidation of the diverse mechanisms through which resistance to ALK TKI emerges, has informed the design of novel therapeutic strategies to improve patients disease outcome. This review summarizes the currently available knowledge regarding ALK physiologic function/structure and neoplastic transforming role, as well as an update on ALK inhibitors and resistance mechanisms along with possible therapeutic strategies that may overcome the development of resistance.
Highlights
Over the last decade, the development of drugs that selectively target driver oncogenes has played an important role to establish novel treatment guidelines in the field of oncology
The anaplastic lymphoma kinase (ALK) gene is located on chromosomal region 2p23 and encodes a highly conserved receptor tyrosine kinase (RTK), which is a member of the insulin receptor superfamily, and is most closely related to leukocyte tyrosine kinase (LTK) [20,21,22]
Following a number of successful in vitro studies [98] showing the efficacy of crizotinib in ALK inhibition, crizotinib entered into early phase I study (PROFILE 1001) presenting a sustained response in locally advanced or metastatic non-small-cell lung cancer (NSCLC) patients carrying the echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion gene [101]
Summary
The development of drugs that selectively target driver oncogenes has played an important role to establish novel treatment guidelines in the field of oncology. Five years follow-up studies have shown that patients treated with imatinib achieved molecular responses and overall survival not different from the general population [2] Another tyrosine kinase extensively explored as a target for TKI treatment is the anaplastic lymphoma kinase (ALK). Four ALK inhibitors (crizotinib, ceritinib, alectinib and brigatinib) have received approval by the FDA for treatment of ALK-rearranged NSCLC, while others such as lorlatinib have shown promising results in early clinical trials [8] The use of these new therapies has improved the quality of life and increased the survival of patients, as demonstrated in their respective clinical trials, with remarkable responses in NSCLC patients carrying ALK-rearrangements [9,10,11,12,13,14,15,16]. We will discuss potential future therapeutic approaches that can be used to tackle TKI resistance and improve patient outcome
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