Cancer

Mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers

Ryohei Katayama, Alice T. Shaw, Tahsin M. Khan, Mari Mino-Kenudson, Benjamin J. Solomon, Balazs Halmos, Nicholas A. Jessop, John C. Wain, Alan Tien Yeo, Cyril Benes, Lisa Drew, Jamal Carlos Saeh, Katherine Crosby, Lecia V. Sequist, A. John Iafrate, Jeffrey A. Engelman

Research output: Contribution to journalArticle

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Abstract

Most anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancers (NSCLCs) are highly responsive to treatment with ALK tyrosine kinase inhibitors (TKIs). However, patients with these cancers invariably relapse, typically within 1 year, because of the development of drug resistance. Herein, we report findings from a series of lung cancer patients (n = 18) with acquired resistance to the ALK TKI crizotinib. In about one-fourth of patients, we identified a diverse array of secondary mutations distributed throughout the ALK TK domain, including new resistance mutations located in the solvent-exposed region of the adenosine triphosphate-binding pocket, as well as amplification of the ALK fusion gene. Next-generation ALK inhibitors, developed to overcome crizotinib resistance, had differing potencies against specific resistance mutations. In addition to secondary ALK mutations and ALK gene amplification, we also identified aberrant activation of other kinases including marked amplification of KIT and increased autophosphorylation of epidermal growth factor receptor in drug-resistant tumors from patients. In a subset of patients, we found evidence of multiple resistance mechanisms developing simultaneously. These results highlight the unique features of TKI resistance in ALK-positive NSCLCs and provide the rationale for pursuing combinatorial therapeutics that are tailored to the precise resistance mechanisms identified in patients who relapse on crizotinib treatment.

Original languageEnglish (US)
JournalScience Translational Medicine
Volume4
Issue number120
DOIs
StatePublished - Feb 8 2012
Externally publishedYes

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Lung Neoplasms
Neoplasms
Protein-Tyrosine Kinases
Mutation
Non-Small Cell Lung Carcinoma
crizotinib
anaplastic lymphoma kinase
Recurrence
Gene Amplification
Gene Fusion
Epidermal Growth Factor Receptor
Drug Resistance
Phosphotransferases
Therapeutics
Adenosine Triphosphate
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Katayama, R., Shaw, A. T., Khan, T. M., Mino-Kenudson, M., Solomon, B. J., Halmos, B., ... Engelman, J. A. (2012). Cancer: Mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers. Science Translational Medicine, 4(120). https://doi.org/10.1126/scitranslmed.3003316

Cancer : Mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers. / Katayama, Ryohei; Shaw, Alice T.; Khan, Tahsin M.; Mino-Kenudson, Mari; Solomon, Benjamin J.; Halmos, Balazs; Jessop, Nicholas A.; Wain, John C.; Yeo, Alan Tien; Benes, Cyril; Drew, Lisa; Saeh, Jamal Carlos; Crosby, Katherine; Sequist, Lecia V.; Iafrate, A. John; Engelman, Jeffrey A.

In: Science Translational Medicine, Vol. 4, No. 120, 08.02.2012.

Research output: Contribution to journalArticle

Katayama, R, Shaw, AT, Khan, TM, Mino-Kenudson, M, Solomon, BJ, Halmos, B, Jessop, NA, Wain, JC, Yeo, AT, Benes, C, Drew, L, Saeh, JC, Crosby, K, Sequist, LV, Iafrate, AJ & Engelman, JA 2012, 'Cancer: Mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers', Science Translational Medicine, vol. 4, no. 120. https://doi.org/10.1126/scitranslmed.3003316
Katayama, Ryohei ; Shaw, Alice T. ; Khan, Tahsin M. ; Mino-Kenudson, Mari ; Solomon, Benjamin J. ; Halmos, Balazs ; Jessop, Nicholas A. ; Wain, John C. ; Yeo, Alan Tien ; Benes, Cyril ; Drew, Lisa ; Saeh, Jamal Carlos ; Crosby, Katherine ; Sequist, Lecia V. ; Iafrate, A. John ; Engelman, Jeffrey A. / Cancer : Mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers. In: Science Translational Medicine. 2012 ; Vol. 4, No. 120.
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