Reference Detail

Ref Type

Journal Article

PMID

(24675041)

Authors

Friboulet L, Li N, Katayama R, Lee CC, Gainor JF, Crystal AS, Michellys PY, Awad MM, Yanagitani N, Kim S, Pferdekamper AC, Li J, Kasibhatla S, Sun F, Sun X, Hua S, McNamara P, Mahmood S, Lockerman EL, Fujita N, Nishio M, Harris JL, Shaw AT, Engelman JA

Title

The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer discovery	4	6	2014 Jun	662-673	Cancer Discov

URL

Abstract Text

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.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.

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Molecular Profile	Treatment Approach
EML4 - ALK ALK G1269A	Ceritinib
EML4 - ALK ALK S1206Y	Ceritinib
EML4 - ALK ALK L1196M	Ceritinib

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
ALK	F1174V	missense	gain of function - predicted	ALK F1174V lies within the protein kinase domain of the Alk protein (UniProt.org). F1174V results in constitutive activation of the Alk protein in cell culture (PMID: 21242967) and has been demonstrated to occur as a secondary resistance mutation in the context of ALK fusions (PMID: 24675041), and therefore, is predicted to lead to a gain of Alk protein function.	Y
ALK	L1152P	missense	unknown	ALK L1152P lies within the protein kinase domain of the Alk protein (UniProt.org). L1152P has been demonstrated to confer drug resistance in the context of ALK rearrangement in culture (PMID: 24675041), but has not been biochemically characterized and therefore, its effect on Alk protein function is unknown (PubMed, Apr 2024).	Y
ALK	S1206Y	missense	unknown	ALK S1206Y lies within the protein kinase domain of the Alk protein (UniProt.org). S1206Y has been demonstrated to occur as a secondary drug resistance mutation in the context of ALK rearrangements (PMID: 22277784, PMID: 24675041, PMID: 25727400), but has not been biochemically characterized and therefore, its effect on Alk protein function is unknown (PubMed, Aug 2024).	Y

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
EML4 - ALK ALK G1269A	lung non-small cell carcinoma	sensitive	Ceritinib	Preclinical - Cell culture	Actionable	In a preclinical study, human lung cancer cell lines harboring EML4-ALK with ALK G1269A demonstrated sensitivity to Zykadia (ceritinib) in culture (PMID: 24675041).	24675041
EML4 - ALK ALK L1152P	Advanced Solid Tumor	resistant	Crizotinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing EML4-ALK with ALK L1152P demonstrated resistance to Xalkori (crizotinib) in culture (PMID: 24675041).	24675041
EML4 - ALK ALK G1269A	lung non-small cell carcinoma	resistant	Crizotinib	Preclinical - Cell culture	Actionable	In a preclinical study, human lung cancer cell lines expressing ALK G1269A in the context of EML4-ALK demonstrated resistance to Xalkori (crizotinib) in culture (PMID: 24675041).	24675041
EML4 - ALK ALK C1156Y	lung non-small cell carcinoma	conflicting	Ceritinib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Zykadia (ceritinib) demonstrated tumor growth inhibition in xenograft models of a human non-small cell lung cancer cell line harboring EML4-ALK with ALK C1156Y when compared to Xalkori (crizotinib) (PMID: 24675041).	24675041
EML4 - ALK ALK F1174C	lung non-small cell carcinoma	resistant	Ceritinib	Case Reports/Case Series	Actionable	In a clinical case study, a non-small cell lung carcinoma patient harboring EML4-ALK who developed resistance to Xalkori (crizotinib) treatment was subsequently treated with Zykadia (ceritinib), eventually progressed, and was found to have acquired ALK F1174C (PMID: 24675041).	24675041
EML4 - ALK ALK S1206Y	Advanced Solid Tumor	sensitive	Ceritinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing EML4-ALK with ALK S1206Y demonstrated growth inhibition with Zykadia (ceritinib) treatment in culture (PMID: 24675041).	24675041
EML4 - ALK ALK G1202R	lung non-small cell carcinoma	resistant	Ceritinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing EML4-ALK with ALK G1202R were insensitive to Zykadia (ceritinib) in culture (PMID: 24675041).	24675041
EML4 - ALK ALK G1202R	lung non-small cell carcinoma	resistant	Ceritinib	Case Reports/Case Series	Actionable	In a clinical case study, a non-small cell lung carcinoma patient harboring EML4-ALK who acquired the secondary drug resistance mutation, ALK S1206Y, when treated with Xalkori (crizotinib) was subsequently treated with Zykadia (ceritinib), developed drug resistance, and was then found to have lost the ALK S1206Y mutation, but gained ALK G1202R (PMID: 24675041).	24675041
EML4 - ALK ALK F1174V ALK G1202R	lung non-small cell carcinoma	sensitive	Ceritinib	Case Reports/Case Series	Actionable	In a clinical case study, a non-small cell lung carcinoma patient harboring EML4-ALK who was previously treated with Xalkori (crizotinib) and subsequently developed the resistance mutation, ALK G1269A, was treated with Zykadia (ceritinib), later progressed, and was found to have lost ALK G1269A, but gained ALK F1174V and ALK G1202R (PMID: 24675041).	24675041
EML4 - ALK ALK L1196M	lung non-small cell carcinoma	sensitive	Ceritinib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Zykadia (ceritinib) inhibited cell survival and PI3K/AKT, MEK/ERK, and mTOR signaling in two human non-small cell lung carcinoma cell lines harboring the Xalkori (crizotinib) resistance mutation EML4-ALK ALK L1196M in culture and inhibited tumor growth in xenograft models of one of those cell lines (PMID: 24675041).	24675041
EML4 - ALK ALK C1156Y	Advanced Solid Tumor	predicted - sensitive	Ceritinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed human cells expressing ALK C1156Y in the context of EML4-ALK demonstrated minimal sensitivity to Zykadia (ceritinib) in culture (PMID: 24675041).	24675041