ArticleCancer medicine2015
Activity of second-generation ALK inhibitors against crizotinib-resistant mutants in an NPM-ALK model compared to EML4-ALK.
Article in Cancer medicine, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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Who cites it
41 citing papers in PubMed, 87 citations in OpenAlex.
- Phase II study of ceritinib in alectinib-pretreated patients with anaplastic lymphoma kinase-rearranged metastatic non-small-cell lung cancer in Japan: ASCEND-9.Cancer science · 2018Trial
- A structure-based virtual screening approach to identify novel anaplastic lymphoma kinase inhibitors.Journal of molecular modeling · 2026Article
- Stalling the Enemy: Targeting Nsp13 for Next-Generation SARS-CoV-2 Antivirals.International journal of molecular sciences · 2026Article
- Mechanistic models position ceritinib as a nuclear integrity disrupting therapy in pediatric liver tumors.Journal of experimental & clinical cancer research : CR · 2025Article
- [Recent Advances in the Treatment of Non-small Cell Lung Cancer with Brigatinib].Zhongguo fei ai za zhi = Chinese journal of lung cancer · 2025Review
- OKAIN: A comprehensive oncology knowledge base for the interpretation of clinically actionable alterations.Open medicine (Warsaw, Poland) · 2025Article
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- The molecular features of lung cancer stem cells in dedifferentiation process-driven epigenetic alterations.The Journal of biological chemistry · 2024Review
- Proteolysis Targeting Chimera Agents (PROTACs): New Hope for Overcoming the Resistance Mechanisms in Oncogene-Addicted Non-Small Cell Lung Cancer.International journal of molecular sciences · 2024Review
- Discovery of novel 2-aminopyridine derivatives as ROS1 and ALK dual inhibitors to combat drug-resistant mutants including ROS1Journal of enzyme inhibition and medicinal chemistry · 2023Article
- Therapeutic Advances of Rare ALK Fusions in Non-Small Cell Lung Cancer.Current oncology (Toronto, Ont.) · 2022Review
- ALK fusion promotes metabolic reprogramming of cancer cells by transcriptionally upregulating PFKFB3.Oncogene · 2022Article
- Case report: NovelFrontiers in oncology · 2022Article
- Review
- Head to head evaluation of second generation ALK inhibitors brigatinib and alectinib as first-line treatment for ALK+ NSCLC using anOncotarget · 2021Article
- Article
- Activation of IGF-1R pathway and NPM-ALK G1269A mutation confer resistance to crizotinib treatment in NPM-ALK positive lymphoma.Investigational new drugs · 2020Article
- Next-generation sequencing to dynamically detect mechanisms of resistance toTranslational lung cancer research · 2020Article
- Role of liquid biopsy in oncogene-addicted non-small cell lung cancer.Translational lung cancer research · 2019Review
- Dual inhibition of IGF-IR and ALK as an effective strategy to eradicate NPM-ALKJournal of hematology & oncology · 2019Article
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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