Abstract
Anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor involved in both solid and hematological tumors. About 80% of ALK-positive anaplastic large-cell lymphoma (ALCL) cases are characterized by the t(2;5)(p23;q35) translocation, encoding for the aberrant fusion protein nucleophosmin (NPM)-ALK, whereas 5% of non-small-cell lung cancer (NSCLC) patients carry the inv(2)(p21;p23) rearrangement, encoding for the echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion. The ALK/c-MET/ROS inhibitor crizotinib successfully improved the treatment of ALK-driven diseases. However, several cases of resistance appeared in NSCLC patients, and ALK amino acid substitutions were identified as a leading cause of resistance to crizotinib. Second-generation ALK inhibitors have been developed in order to overcome crizotinib resistance. In this work, we profiled in vitro the activity of crizotinib, AP26113, ASP3026, alectinib, and ceritinib against six mutated forms of ALK associated with clinical resistance to crizotinib (C1156Y, L1196M, L1152R, G1202R, G1269A, and S1206Y) and provide a classification of mutants according to their level of sensitivity/resistance to the drugs. Since the biological activity of ALK mutations extends beyond the specific type of fusion, both NPM-ALK- and EML4-ALK-positive cellular models were used. Our data revealed that most mutants may be targeted by using different inhibitors. One relevant exception is represented by the G1202R substitution, which was highly resistant to all drugs (>10-fold increased IC50 compared to wild type) and may represent the most challenging mutation to overcome. These results provide a prediction of cross-resistance of known crizotinib-resistant mutations against all second-generation tyrosine kinase inhibitors (TKIs) clinically available, and therefore could be a useful tool to help clinicians in the management of crizotinib-resistance cases.
Highlights
Anaplastic lymphoma kinase (ALK) belongs to the insulin receptor protein-tyrosine kinase superfamily [1]
About 80% of ALK-positive anaplastic large-cell lymphoma (ALCL) cases are characterized by the t(2;5)(p23;q35) translocation, encoding for the aberrant fusion protein nucleophosmin (NPM)ALK, whereas 5% of non-small-cell lung cancer (NSCLC) patients carry the inv (2)(p21;p23) rearrangement, encoding for the echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion
Second-generation ALK inhibitors have been developed in order to overcome crizotinib resistance
Summary
Anaplastic lymphoma kinase (ALK) belongs to the insulin receptor protein-tyrosine kinase superfamily [1]. The first evidence of ALK oncogenic properties emerged in 1994, when the fusion protein nucleophosmin (NPM)-ALK originated by the chromosomal translocation t(2;5)(p23;q35) was identified and associated with an aggressive form of nonHodgkin T-cell lymphoma, known as anaplastic large-cell lymphoma (ALCL) [3]. Several dysregulated or aberrant ALK forms have since been discovered as the cause of hematopoietic and non-hematopoietic malignancies, such as diffuse large B-cell lymphoma (DLBCL) [4], inflammatory myofibroblastic tumor (IMT) [5], neuroblastoma [6], anaplastic thyroid cancer [7], rhabdomyosarcoma [8], non-small-cell lung cancer (NSCLC) [9], and other a 2015 The Authors.
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