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The ALK Inhibitor Ceritinib Overcomes Crizotinib Resistance in Non–Small Cell Lung Cancer
Open accessAbstract
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
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Cites
Identification of the transforming EML4–ALK fusion gene in non-small-cell lung cancer
Soda, M., Choi, Y. L., Enomoto, M., Takada, S., Yamashita, Y., Ishikawa, S., Fujiwara, S.-I., Watanabe, H., Kurashina, K., Hatanaka, H., et al. (2007) · Nature · doi:10.1038/nature05945 · Cited by 5,439
Ceritinib in ALK -Rearranged Non–Small-Cell Lung Cancer
Shaw, A. T., Kim, D.-W., Mehra, R., Tan, D. S. W., Felip, E., Chow, L. Q. M., Camidge, D. R., Vansteenkiste, J., Sharma, S., De Pas, T., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1311107 · Cited by 1,495
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Soria, J.-C., Tan, D. S. W., Chiari, R., Wu, Y.-L., Paz-Ares, L., Wolf, J., Geater, S. L., Orlov, S., Cortinovis, D., Yu, C.-J., et al. (2017) · The Lancet · doi:10.1016/s0140-6736(17)30123-x · Cited by 1,151
Gridelli, C., Rossi, A., Carbone, D. P., Guarize, J., Karachaliou, N., Mok, T., Petrella, F., Spaggiari, L., & Rosell, R. (2015) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2015.9 · Cited by 1,083
Roskoski, R. (2016) · Pharmacological Research · doi:10.1016/j.phrs.2015.10.021 · Cited by 886
Cell death-based treatment of lung adenocarcinoma
Denisenko, T. V., Budkevich, I. N., & Zhivotovsky, B. (2018) · Cell Death & Disease · doi:10.1038/s41419-017-0063-y · Cited by 768
Patient-derived models of acquired resistance can identify effective drug combinations for cancer
Crystal, A. S., Shaw, A. T., Sequist, L. V., Friboulet, L., Niederst, M. J., Lockerman, E. L., Frias, R. L., Gainor, J. F., Amzallag, A., Greninger, P., et al. (2014) · Science · doi:10.1126/science.1254721 · Cited by 708
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Metadata
- Authors
- Friboulet, L., Li, N., Katayama, R., Lee, C. C., Gainor, J. F., Crystal, A. S., Michellys, P.-Y., Awad, M. M., Yanagitani, N., Kim, S., Pferdekamper, A. C., Li, J., Kasibhatla, S., Sun, F., Sun, X., Hua, S., McNamara, P., Mahmood, S., Lockerman, E. L., Fujita, N., Nishio, M., Harris, J. L., Shaw, A. T., & Engelman, J. A.
- Venue
- Cancer Discovery
- Published
- 2014-06-01
- Volume
- 4
- Issue
- 6
- Pages
- 662-673
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- OpenAlex
- W2123394258
- Cited by
- 840
- References
- 2
- FWCI
- 86.27
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Friboulet, L., Li, N., Katayama, R., Lee, C. C., Gainor, J. F., Crystal, A. S., Michellys, P.-Y., Awad, M. M., Yanagitani, N., Kim, S., Pferdekamper, A. C., Li, J., Kasibhatla, S., Sun, F., Sun, X., Hua, S., McNamara, P., Mahmood, S., Lockerman, E. L., . . . Engelman, J. A. (2014). The ALK Inhibitor Ceritinib Overcomes Crizotinib Resistance in Non–Small Cell Lung Cancer. Cancer Discovery. https://doi.org/10.1158/2159-8290.cd-13-0846
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