TY - JOUR
T1 - The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer
AU - Friboulet, Luc
AU - Li, Nanxin
AU - Katayama, Ryohei
AU - Lee, Christian C.
AU - Gainor, Justin F.
AU - Crystal, Adam S.
AU - Michellys, Pierre Yves
AU - Awad, Mark M.
AU - Yanagitani, Noriko
AU - Kim, Sungjoon
AU - Pferdekamper, Anne Marie C.
AU - Li, Jie
AU - Kasibhatla, Shailaja
AU - Sun, Frank
AU - Sun, Xiuying
AU - Hua, Su
AU - McNamara, Peter
AU - Mahmood, Sidra
AU - Lockerman, Elizabeth L.
AU - Fujita, Naoya
AU - Nishio, Makoto
AU - Harris, Jennifer L.
AU - Shaw, Alice T.
AU - Engelman, Jeffrey A.
PY - 2014/1/1
Y1 - 2014/1/1
N2 - 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 crizotinibresistant 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.
AB - 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 crizotinibresistant 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.
UR - http://www.scopus.com/inward/record.url?scp=84903466222&partnerID=8YFLogxK
U2 - 10.1158/2159-8290.CD-13-0846
DO - 10.1158/2159-8290.CD-13-0846
M3 - Article
C2 - 24675041
AN - SCOPUS:84903466222
SN - 2159-8274
VL - 4
SP - 662
EP - 673
JO - Cancer Discovery
JF - Cancer Discovery
IS - 6
ER -