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Clin Cancer Res. 2015 Sep 1;21(17):3913-23. doi: 10.1158/1078-0432.CCR-14-2789. Epub 2015 May 6.

EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors.

Author information

1
Lowe Center for Thoracic Oncology, Dana Farber Cancer Institute, Boston, Massachusetts.
2
Department of Cancer Biology, Dana Farber Cancer Institute, Boston, Massachusetts. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts.
3
Department of Cancer Biology, Dana Farber Cancer Institute, Boston, Massachusetts. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts. Institute of Systems Biomedicine, Department of Biophysics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
4
Department of Cancer Biology, Dana Farber Cancer Institute, Boston, Massachusetts. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts. pasi_janne@dfci.harvard.edu Nathanael_Gray@dfci.harvard.edu.
5
Lowe Center for Thoracic Oncology, Dana Farber Cancer Institute, Boston, Massachusetts. Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts. Belfer Institute for Applied Cancer Science, Dana Farber Cancer Institute, Boston, Massachusetts. pasi_janne@dfci.harvard.edu Nathanael_Gray@dfci.harvard.edu.

Abstract

PURPOSE:

Mutant selective irreversible pyrimidine-based EGFR kinase inhibitors, including WZ4002, CO-1686, and AZD9291, are effective in preclinical models and in lung cancer patients harboring the EGFR T790M gefitinib/erlotinib resistance mutation. However, little is known about how cancers develop acquired resistance to this class of EGFR inhibitors. We sought to identify and study EGFR mutations that confer resistance to this class of agents.

EXPERIMENTAL DESIGN:

We performed an N-ethyl-N-nitrosourea (ENU) mutagenesis screen in EGFR-mutant (sensitizing alone or with concurrent EGFR T790M) Ba/F3 cells and selected drug-resistant clones. We evaluated the sensitivity of EGFR inhibitors in models harboring drug-resistant EGFR mutations.

RESULTS:

We identified 3 major drug resistance mutations. EGFR L718Q, L844V, and C797S cause resistance to both WZ4002 and CO-1686 while, in contrast, only EGFR C797S leads to AZD9291 resistance. Cells containing an EGFR-sensitizing mutation, Del 19 or L858R, in conjunction with L718Q, L844V, or C797S retain sensitivity to quinazoline-based EGFR inhibitors, gefitinib and afatinib. The C797S mutation, in the presence of Del 19 or L858R and T790M, causes resistance to all current EGFR inhibitors, but L858R/T790M/C797S remains partially sensitive to cetuximab which leads to disruption of EGFR dimerization.

CONCLUSIONS:

Our findings provide insights into resistance mechanisms to irreversible pyrimidine-based EGFR inhibitors and identify specific genomic contexts in which sensitivity is retained to existing clinical EGFR inhibitors. These findings will guide the development of new strategies to inhibit EGFR.

PMID:
25948633
PMCID:
PMC4791951
DOI:
10.1158/1078-0432.CCR-14-2789
[Indexed for MEDLINE]
Free PMC Article

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