論文 - 詳細
| RRC ID | 68843 |
|---|---|
| 著者 | Katayama R, Friboulet L, Koike S, Lockerman EL, Khan TM, Gainor JF, Iafrate AJ, Takeuchi K, Taiji M, Okuno Y, Fujita N, Engelman JA, Shaw AT. |
| タイトル | Two novel ALK mutations mediate acquired resistance to the next-generation ALK inhibitor alectinib. |
| ジャーナル | Clin Cancer Res |
| Abstract |
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. |
| 巻・号 | 20(22) |
| ページ | 5686-96 |
| 公開日 | 2014-11-15 |
| DOI | 10.1158/1078-0432.CCR-14-1511 |
| PII | 1078-0432.CCR-14-1511 |
| PMID | 25228534 |
| PMC | PMC4233168 |
| MeSH | Anaplastic Lymphoma Kinase Benzoquinones / pharmacology Carbazoles / pharmacology* Carbazoles / therapeutic use Carcinoma, Non-Small-Cell Lung / diagnostic imaging Carcinoma, Non-Small-Cell Lung / drug therapy Carcinoma, Non-Small-Cell Lung / genetics Carcinoma, Non-Small-Cell Lung / metabolism Cell Line, Tumor Crizotinib DNA Mutational Analysis Dose-Response Relationship, Drug Drug Resistance, Neoplasm / genetics* HSP90 Heat-Shock Proteins / antagonists & inhibitors Humans Inhibitory Concentration 50 Lactams, Macrocyclic / pharmacology Lung Neoplasms / diagnostic imaging Lung Neoplasms / drug therapy Lung Neoplasms / genetics Lung Neoplasms / metabolism Models, Molecular Mutation* Piperidines / pharmacology* Piperidines / therapeutic use Protein Conformation Protein Kinase Inhibitors / pharmacology* Protein Kinase Inhibitors / therapeutic use Pyrazoles / pharmacology Pyrazoles / therapeutic use Pyridines / pharmacology Pyridines / therapeutic use Receptor Protein-Tyrosine Kinases / antagonists & inhibitors* Receptor Protein-Tyrosine Kinases / chemistry Receptor Protein-Tyrosine Kinases / genetics* Tomography, X-Ray Computed |
| IF | 10.107 |
| リソース情報 | |
| ヒト・動物細胞 | Ba/F3 |