Two Novel ALK Mutations Mediate Acquired Resistance to the Next-Generation ALK Inhibitor Alectinib
Autor: | Sumie Koike, Ryohei Katayama, Jeffrey A. Engelman, Kengo Takeuchi, Makoto Taiji, Alice T. Shaw, Justin F. Gainor, Luc Friboulet, Elizabeth L. Lockerman, Tahsin M. Khan, A. John Iafrate, Yasushi Okuno, Naoya Fujita |
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Rok vydání: | 2014 |
Předmět: |
Models
Molecular Alectinib Cancer Research Lung Neoplasms Protein Conformation Pyridines medicine.drug_class Lactams Macrocyclic DNA Mutational Analysis Carbazoles medicine.disease_cause Article Tyrosine-kinase inhibitor Inhibitory Concentration 50 Crizotinib Piperidines Carcinoma Non-Small-Cell Lung Cell Line Tumor hemic and lymphatic diseases Benzoquinones medicine Humans Anaplastic lymphoma kinase Anaplastic Lymphoma Kinase HSP90 Heat-Shock Proteins Protein Kinase Inhibitors Genetics Mutation Dose-Response Relationship Drug Ceritinib business.industry Receptor Protein-Tyrosine Kinases Cancer medicine.disease respiratory tract diseases ALK inhibitor Oncology Drug Resistance Neoplasm Cancer research Pyrazoles Tomography X-Ray Computed business medicine.drug |
Zdroj: | Clinical Cancer Research. 20:5686-5696 |
ISSN: | 1557-3265 1078-0432 |
Popis: | Purpose: The first-generation ALK tyrosine kinase inhibitor (TKI) crizotinib is a standard therapy for patients with ALK-rearranged non–small cell lung cancer (NSCLC). Several next-generation ALK-TKIs have entered the clinic and have shown promising activity in crizotinib-resistant patients. As patients still relapse even on these next-generation ALK-TKIs, we examined mechanisms of resistance to the next-generation ALK-TKI alectinib and potential strategies to overcome this resistance. Experimental Design: We established a cell line model of alectinib resistance, and analyzed a resistant tumor specimen from a patient who had relapsed on alectinib. We developed Ba/F3 models harboring alectinib-resistant ALK mutations and evaluated the potency of other next-generation ALK-TKIs in these models. We tested the antitumor activity of the next-generation ALK-TKI ceritinib in the patient with acquired resistance to alectinib. To elucidate structure–activity relationships of ALK mutations, we performed computational thermodynamic simulation with MP-CAFEE. Results: We identified a novel V1180L gatekeeper mutation from the cell line model and a second novel I1171T mutation from the patient who developed resistance to alectinib. Both ALK mutations conferred resistance to alectinib as well as to crizotinib, but were sensitive to ceritinib and other next-generation ALK-TKIs. Treatment of the patient with ceritinib led to a marked response. Thermodynamics simulation suggests that both mutations lead to distinct structural alterations that decrease the binding affinity with alectinib. Conclusions: We have identified two novel ALK mutations arising after alectinib exposure that are sensitive to other next-generation ALK-TKIs. The ability of ceritinib to overcome alectinib-resistance mutations suggests a potential role for sequential therapy with multiple next-generation ALK-TKIs. Clin Cancer Res; 20(22); 5686–96. ©2014 AACR. |
Databáze: | OpenAIRE |
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