The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer
By L. Friboulet, Nanxin Li, Ryohei Katayama, Christian C. Lee, J. Gainor, A. Crystal, P. Michellys, M. Awad, N. Yanagitani, Sungjoon Kim and 14 more. Cancer Discovery, 2014
763 citations recorded by the source corpus.
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. Interrogation of in vitro and in vivo models of acquired resistance to crizotinib, including cell lines established from biopsies of crizotinib-resistant NSCLC patients revealed that ceritinib potently overcomes crizotinib resistance mutations. In particular, ceritinib effectively inhibits ALK harboring L1196M, G1269A, I1171T and S1206Y mutations, and a co-crystal 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 were identified in 5 out 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.
View Paper: https://www.semanticscholar.org/paper/ef08289ac82291af10dbb2dda85910af0f63253a
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- B. Chan
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- María Gomez-Caraballo
- H. Rupasinghe
- E. Lifshits
Citations in the corpus
- Kinase-targeted cancer therapies: progress, challenges and future directions (2018, background): “imatinib, 28 kinase inhibitors have been approved by FDA with Brigatinib and Osimertinib being the latest approvals [91, 92].”
- Patient-derived Models of Acquired Resistance Can Identify Effective Drug Combinations for Cancer (2014, methodology): “described (27), but the combination resulted in a more sustained response (Fig.”
- Targeted therapy for non-small cell lung cancer: current standards and the promise of the future. (2015, background): “Particularly encouraging is that response rates were similar for patients with various known resistance mechanisms as well as those without an identifiable mutation (114).”
- Molecular Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in ALK-Rearranged Lung Cancer (2016, unknown): “G1202R maps to the solvent-exposed region of the ALK kinase, where the bulkier, charged side chain is thought to lead to steric hindrance of most ALK inhibitors (6, 17, 25).”