The ALK Inhibitor Ceritinib Overcomes Crizotinib Resistance in Non–Small Cell Lung Cancer
Tóm tắt
Non–small cell lung cancers (NSCLC) harboring anaplastic lymphoma kinase (ALK) gene rearrangements invariably develop resistance to the ALK tyrosine kinase inhibitor (TKI) crizotinib. Herein, we report the first preclinical evaluation of the next-generation ALK TKI, ceritinib (LDK378), in the setting of crizotinib resistance. An interrogation of in vitro and in vivo models of acquired resistance to crizotinib, including cell lines established from biopsies of patients with crizotinib-resistant NSCLC, revealed that ceritinib potently overcomes crizotinib-resistant mutations. In particular, ceritinib effectively inhibits ALK harboring L1196M, G1269A, I1171T, and S1206Y mutations, and a cocrystal structure of ceritinib bound to ALK provides structural bases for this increased potency. However, we observed that ceritinib did not overcome two crizotinib-resistant ALK mutations, G1202R and F1174C, and one of these mutations was identified in 5 of 11 biopsies from patients with acquired resistance to ceritinib. Altogether, our results demonstrate that ceritinib can overcome crizotinib resistance, consistent with clinical data showing marked efficacy of ceritinib in patients with crizotinib-resistant disease.
Significance: The second-generation ALK inhibitor ceritinib can overcome several crizotinib-resistant mutations and is potent against several in vitro and in vivo laboratory models of acquired resistance to crizotinib. These findings provide the molecular basis for the marked clinical activity of ceritinib in patients with ALK-positive NSCLC with crizotinib-resistant disease. Cancer Discov; 4(6); 662–73. ©2014 AACR.
See related commentary by Ramalingam and Khuri, p. 634
This article is highlighted in the In This Issue feature, p. 621
Từ khóa
Tài liệu tham khảo
Kwak, 2010, Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer, N Engl J Med, 363, 1693, 10.1056/NEJMoa1006448
Soda, 2007, Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer, Nature, 448, 561, 10.1038/nature05945
Koivunen, 2008, EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer, Clin Cancer Res, 14, 4275, 10.1158/1078-0432.CCR-08-0168
Doebele, 2012, Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer, Clin Cancer Res, 18, 1472, 10.1158/1078-0432.CCR-11-2906
Gainor, 2013, ALK rearrangements are mutually exclusive with mutations in EGFR or KRAS: an analysis of 1,683 patients with non-small cell lung cancer, Clin Cancer Res, 19, 4273, 10.1158/1078-0432.CCR-13-0318
Katayama, 2012, Mechanisms of acquired crizotinib resistance in ALK-rearranged lung Cancers, Sci Transl Med, 4, 120ra117, 10.1126/scitranslmed.3003316
Choi, 2010, EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors, N Engl J Med, 363, 1734, 10.1056/NEJMoa1007478
Lovly, 2012, Escaping ALK inhibition: mechanisms of and strategies to overcome resistance, Sci Transl Med, 4, 120ps122, 10.1126/scitranslmed.3003728
Sasaki, 2011, A novel ALK secondary mutation and EGFR signaling cause resistance to ALK kinase inhibitors, Cancer Res, 71, 6051, 10.1158/0008-5472.CAN-11-1340
Sasaki, 2010, The neuroblastoma-associated F1174L ALK mutation causes resistance to an ALK kinase inhibitor in ALK-translocated cancers, Cancer Res, 70, 10038, 10.1158/0008-5472.CAN-10-2956
Katayama, 2011, Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK, Proc Natl Acad Sci U S A, 108, 7535, 10.1073/pnas.1019559108
Marsilje, 2013, Synthesis, structure-activity relationships, and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase (ALK) inhibitor 5-Chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulf onyl)phenyl)pyrimidine-2,4-diamine (LDK378) currently in phase 1 and phase 2 clinical trials, J Med Chem, 56, 5675, 10.1021/jm400402q
Shaw, 2014, Ceritinib in ALK-rearranged non-small-cell lung cancer, N Engl J Med, 370, 1189, 10.1056/NEJMoa1311107
2013, Early Results Promising for LKD378 in ALK-positive NSCLC, Cancer Discov, 3, OF5, 10.1158/2159-8290.CD-NB2013-091
FDA, Center for Drug Evaluation and Research
Cui, 2010, Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK), J Med Chem, 54, 6342, 10.1021/jm2007613
Chand, 2013, Cell culture and Drosophila model systems define three classes of anaplastic lymphoma kinase mutations in neuroblastoma, Dis Models & Mech, 6, 373
Lee, 2010, Crystal structure of the ALK (anaplastic lymphoma kinase) catalytic domain, Biochem J, 430, 425, 10.1042/BJ20100609