The ALK Inhibitor Ceritinib Overcomes Crizotinib Resistance in Non-Small Cell Lung Cancer

被引：683

作者：

Friboulet, Luc ^{[1
,2
]}

Li, Nanxin

Katayama, Ryohei ^{[1
,2
,4
]}

Lee, Christian C. ^{[3
]}

Gainor, Justin F. ^{[1
,2
]}

Crystal, Adam S. ^{[1
,2
]}

Michellys, Pierre-Yves ^{[3
]}

Awad, Mark M. ^{[1
,2
]}

Yanagitani, Noriko ^{[5
]}

Kim, Sungjoon ^{[3
]}

Pferdekamper, AnneMarie C. ^{[3
]}

Li, Jie ^{[3
]}

Kasibhatla, Shailaja ^{[3
]}

Sun, Frank ^{[3
]}

Sun, Xiuying ^{[3
]}

Hua, Su ^{[3
]}

McNamara, Peter ^{[3
]}

Mahmood, Sidra ^{[1
,2
]}

Lockerman, Elizabeth L. ^{[1
,2
]}

Fujita, Naoya ^{[4
]}

Nishio, Makoto ^{[5
]}

Harris, Jennifer L. ^{[3
]}

Shaw, Alice T. ^{[1
,2
]}

Engelman, Jeffrey A. ^{[1
,2
]}

机构：

[1] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA 02129 USA

[2] Harvard Univ, Sch Med, Dept Med, Boston, MA USA

[3] Novartis Res Fdn, Genom Inst, San Diego, CA USA

[4] Japanese Fdn Canc Res, Ctr Canc Chemotherapy, Tokyo 170, Japan

[5] Japanese Fdn Canc Res, Canc Inst Hosp, Tokyo, Japan

来源：

CANCER DISCOVERY | 2014年 / 4卷 / 06期

关键词：

EML4-ALK FUSION GENE; KINASE INHIBITOR; MUTATIONS; EGFR;

D O I：

10.1158/2159-8290.CD-13-0846

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：662 / 673

页数：12

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