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Mol Cancer Ther. 2015 Feb;14(2):542-52. doi: 10.1158/1535-7163.MCT-14-0723. Epub 2014 Dec 4.

Optimizing the sequence of anti-EGFR-targeted therapy in EGFR-mutant lung cancer.

Author information

1
Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee.
2
Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee.
3
Antitumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, New York.
4
Department of Pathology, Yale University School of Medicine, New Haven, Connecticut. Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut.
5
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
6
Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, Tennessee.
7
Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee.
8
Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee.
9
Department of Pathology, Yale University School of Medicine, New Haven, Connecticut. Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut. Department of Medicine, Yale University School of Medicine, New Haven, Connecticut.
10
Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee. Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee. Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee.
11
Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee. Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
12
AstraZeneca Oncology Innovative Medicines, Alderley Park, Macclesfield, Cheshire, United Kingdom.
13
Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee. Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee. Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee. william.pao@vanderbilt.edu.

Abstract

Metastatic EGFR-mutant lung cancers are sensitive to the first- and second-generation EGFR tyrosine kinase inhibitors (TKIs) gefitinib, erlotinib, and afatinib, but resistance develops. Acquired resistance to gefitinib or erlotinib occurs most commonly (>50%) via the emergence of a second-site EGFR mutation, T790M. Two strategies to overcome T790M-mediated resistance are dual inhibition of EGFR with afatinib plus the anti-EGFR antibody cetuximab (A+C), or mutant-specific EGFR inhibition with AZD9291. A+C and AZD9291 are now also being tested as first-line therapies, but whether these therapies will extend progression-free survival or induce more aggressive forms of resistance in this setting remains unknown. We modeled resistance to multiple generations of anti-EGFR therapies preclinically to understand the effects of sequential treatment with anti-EGFR agents on drug resistance and determine the optimal order of treatment. Using a panel of erlotinib/afatinib-resistant cells, including a novel patient-derived cell line (VP-2), we found that AZD9291 was more potent than A+C at inhibiting cell growth and EGFR signaling in this setting. Four of four xenograft-derived A+C-resistant cell lines displayed in vitro and in vivo sensitivity to AZD9291, but four of four AZD9291-resistant cell lines demonstrated cross-resistance to A+C. Addition of cetuximab to AZD9291 did not confer additive benefit in any preclinical disease setting. This work, emphasizing a mechanistic understanding of the effects of therapies on tumor evolution, provides a framework for future clinical trials testing different treatment sequences. This paradigm is applicable to other tumor types in which multiple generations of inhibitors are now available.

PMID:
25477325
PMCID:
PMC4338015
DOI:
10.1158/1535-7163.MCT-14-0723
[Indexed for MEDLINE]
Free PMC Article

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