title: The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, MA 02129, USA.|Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Luc
authors.initials: L
authors.lastname: Friboulet
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121.
authors.forename: Nanxin
authors.initials: N
authors.lastname: Li
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, MA 02129, USA.|Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.|Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, JAPAN.
authors.forename: Ryohei
authors.initials: R
authors.lastname: Katayama
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121.
authors.forename: Christian C
authors.initials: CC
authors.lastname: Lee
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, MA 02129, USA.|Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Justin F
authors.initials: JF
authors.lastname: Gainor
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, MA 02129, USA.|Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Adam S
authors.initials: AS
authors.lastname: Crystal
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121.
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Michellys
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, MA 02129, USA.|Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Awad
authors.affiliation: Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, JAPAN.
authors.forename: Noriko
authors.initials: N
authors.lastname: Yanagitani
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121.
authors.forename: Sungjoon
authors.initials: S
authors.lastname: Kim
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121.
authors.forename: AnneMarie C
authors.initials: AC
authors.lastname: Pferdekamper
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121.
authors.forename: Shailaja
authors.initials: S
authors.lastname: Kasibhatla
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121.
authors.forename: Frank
authors.initials: F
authors.lastname: Sun
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121.
authors.forename: Xiuying
authors.initials: X
authors.lastname: Sun
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121.
authors.forename: Su
authors.initials: S
authors.lastname: Hua
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121.
authors.forename: Peter
authors.initials: P
authors.lastname: McNamara
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, MA 02129, USA.|Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Sidra
authors.initials: S
authors.lastname: Mahmood
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, MA 02129, USA.|Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Lockerman
authors.affiliation: Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, JAPAN.
authors.forename: Naoya
authors.initials: N
authors.lastname: Fujita
authors.affiliation: Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, JAPAN.
authors.forename: Makoto
authors.initials: M
authors.lastname: Nishio
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Harris
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, MA 02129, USA.|Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Alice T
authors.initials: AT
authors.lastname: Shaw
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, MA 02129, USA.|Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Engelman
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011720:Pyrazoles / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013450:Sulfones / Q000627:therapeutic use*; D047368:Tumor Burden
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; D013450:Sulfones; D000077547:Crizotinib; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; C586847:ceritinib