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Clinical Cancer Research
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Predictive Biomarkers and Personalized Medicine

Mechanisms of Resistance to Crizotinib in Patients with ALK Gene Rearranged Non–Small Cell Lung Cancer

Robert C. Doebele, Amanda B. Pilling, Dara L. Aisner, Tatiana G. Kutateladze, Anh T. Le, Andrew J. Weickhardt, Kimi L. Kondo, Derek J. Linderman, Lynn E. Heasley, Wilbur A. Franklin, Marileila Varella-Garcia and D. Ross Camidge
Robert C. Doebele
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Amanda B. Pilling
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Dara L. Aisner
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Tatiana G. Kutateladze
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Anh T. Le
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Andrew J. Weickhardt
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Kimi L. Kondo
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Derek J. Linderman
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Lynn E. Heasley
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Wilbur A. Franklin
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Marileila Varella-Garcia
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D. Ross Camidge
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DOI: 10.1158/1078-0432.CCR-11-2906 Published March 2012
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Abstract

Purpose: Patients with anaplastic lymphoma kinase (ALK) gene rearrangements often manifest dramatic responses to crizotinib, a small-molecule ALK inhibitor. Unfortunately, not every patient responds and acquired drug resistance inevitably develops in those who do respond. This study aimed to define molecular mechanisms of resistance to crizotinib in patients with ALK+ non–small cell lung cancer (NSCLC).

Experimental Design: We analyzed tissue obtained from 14 patients with ALK+ NSCLC showing evidence of radiologic progression while on crizotinib to define mechanisms of intrinsic and acquired resistance to crizotinib.

Results: Eleven patients had material evaluable for molecular analysis. Four patients (36%) developed secondary mutations in the tyrosine kinase domain of ALK. A novel mutation in the ALK domain, encoding a G1269A amino acid substitution that confers resistance to crizotinib in vitro, was identified in two of these cases. Two patients, one with a resistance mutation, exhibited new onset ALK copy number gain (CNG). One patient showed outgrowth of epidermal growth factor receptor (EGFR) mutant NSCLC without evidence of a persistent ALK gene rearrangement. Two patients exhibited a KRAS mutation, one of which occurred without evidence of a persisting ALK gene rearrangement. One patient showed the emergence of an ALK gene fusion–negative tumor compared with the baseline sample but with no identifiable alternate driver. Two patients retained ALK positivity with no identifiable resistance mechanism.

Conclusions: Crizotinib resistance in ALK+ NSCLC occurs through somatic kinase domain mutations, ALK gene fusion CNG, and emergence of separate oncogenic drivers. Clin Cancer Res; 18(5); 1472–82. ©2012 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Received November 14, 2011.
  • Revision received December 9, 2011.
  • Accepted December 28, 2011.
  • ©2012 American Association for Cancer Research.
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Clinical Cancer Research: 18 (5)
March 2012
Volume 18, Issue 5
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Mechanisms of Resistance to Crizotinib in Patients with ALK Gene Rearranged Non–Small Cell Lung Cancer
Robert C. Doebele, Amanda B. Pilling, Dara L. Aisner, Tatiana G. Kutateladze, Anh T. Le, Andrew J. Weickhardt, Kimi L. Kondo, Derek J. Linderman, Lynn E. Heasley, Wilbur A. Franklin, Marileila Varella-Garcia and D. Ross Camidge
Clin Cancer Res March 1 2012 (18) (5) 1472-1482; DOI: 10.1158/1078-0432.CCR-11-2906

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Mechanisms of Resistance to Crizotinib in Patients with ALK Gene Rearranged Non–Small Cell Lung Cancer
Robert C. Doebele, Amanda B. Pilling, Dara L. Aisner, Tatiana G. Kutateladze, Anh T. Le, Andrew J. Weickhardt, Kimi L. Kondo, Derek J. Linderman, Lynn E. Heasley, Wilbur A. Franklin, Marileila Varella-Garcia and D. Ross Camidge
Clin Cancer Res March 1 2012 (18) (5) 1472-1482; DOI: 10.1158/1078-0432.CCR-11-2906
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Clinical Cancer Research
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