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.