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Prev | Table of Contents | Next Published in Science Translational Medicine Rapid Publication on January 25 2012
Sci Transl Med 8 February 2012:
Vol. 4, Issue 120, p. 120ra17
Sci. Transl. Med. DOI: 10.1126/scitranslmed.3003316
•Research Article
Cancer
Mechanisms of Acquired Crizotinib Resistance in ALK-Rearranged Lung Cancers
Ryohei Katayama1,2,*, Alice T. Shaw1,2,3,*, Tahsin M. Khan1,3, Mari Mino-Kenudson2,4, Benjamin J. Solomon5, Balazs Halmos6, Nicholas A. Jessop1, John C. Wain1,7, Alan Tien Yeo1, Cyril Benes1,2, Lisa Drew8, Jamal Carlos Saeh8, Katherine Crosby9, Lecia V. Sequist1,2, A. John Iafrate2,4 and Jeffrey A. Engelman1,2,†
+ Author Affiliations
1Massachusetts General Hospital Cancer Center, Boston, MA 02129, USA.
2Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
3Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
4Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
5Peter MacCallum Cancer Center, East Melbourne, Victoria 3002, Australia.
6Columbia University Medical Center, New York City, NY 10032, USA.
7Department of Surgery, Harvard Medical School, Boston, MA 02115, USA.
8AstraZeneca R&D Boston, Waltham, MA 02451, USA.
9Cell Signaling Technology Inc., Danvers, MA 01923, USA.
+ Author Notes
?* These authors contributed equally to this work.
?†To whom correspondence should be addressed. E-mail: jengelman@partners.org
AbstractBack to Top
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.
Copyright © 2012, American Association for the Advancement of Science
Citation: R. Katayama, A. T. Shaw, T. M. Khan, M. Mino-Kenudson, B. J. Solomon, B. Halmos, N. A. Jessop, J. C. Wain, A. T. Yeo, C. Benes, L. Drew, J. C. Saeh, K. Crosby, L. V. Sequist, A. J. Iafrate, J. A. Engelman, Mechanisms of Acquired Crizotinib Resistance in ALK-Rearranged Lung Cancers. Sci. Transl. Med. 4, 120ra17 (2012).
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