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Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer
Lucia Regales, … , Katerina A. Politi, William Pao
Lucia Regales, … , Katerina A. Politi, William Pao
Published September 14, 2009
Citation Information: J Clin Invest. 2009;119(10):3000-3010. https://doi.org/10.1172/JCI38746.
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Research Article Oncology

Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer

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Abstract

EGFR is a major anticancer drug target in human epithelial tumors. One effective class of agents is the tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib. These drugs induce dramatic responses in individuals with lung adenocarcinomas characterized by mutations in exons encoding the EGFR tyrosine kinase domain, but disease progression invariably occurs. A major reason for such acquired resistance is the outgrowth of tumor cells with additional TKI-resistant EGFR mutations. Here we used relevant transgenic mouse lung tumor models to evaluate strategies to overcome the most common EGFR TKI resistance mutation, T790M. We treated mice bearing tumors harboring EGFR mutations with a variety of anticancer agents, including a new irreversible EGFR TKI that is under development (BIBW-2992) and the EGFR-specific antibody cetuximab. Surprisingly, we found that only the combination of both agents together induced dramatic shrinkage of erlotinib-resistant tumors harboring the T790M mutation, because together they efficiently depleted both phosphorylated and total EGFR. We suggest that these studies have immediate therapeutic implications for lung cancer patients, as dual targeting with cetuximab and a second-generation EGFR TKI may be an effective strategy to overcome T790M-mediated drug resistance. Moreover, this approach could serve as an important model for targeting other receptor tyrosine kinases activated in human cancers.

Authors

Lucia Regales, Yixuan Gong, Ronglai Shen, Elisa de Stanchina, Igor Vivanco, Aviva Goel, Jason A. Koutcher, Maria Spassova, Ouathek Ouerfelli, Ingo K. Mellinghoff, Maureen F. Zakowski, Katerina A. Politi, William Pao

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Figure 3

The combination of cetuximab and BIBW-2992 induces tumor regressions of mouse lung tumors driven by EGFRL858R+T790M.

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The combination of cetuximab and BIBW-2992 induces tumor regressions of ...
(A) MRI images of lungs from a tumor-bearing C/L858R mouse pretreatment and after treatment with cetuximab for 2 weeks. H&E-stained section from treated C/L858R mouse (right panel) (original magnification, ×40). (B) MRI images of lungs from tumor-bearing C/L+T (top panels) and C/T790M (bottom panels) mice, pretreatment, after 6 days of erlotinib (erloti), and then after 4 weeks of cetuximab. H&E-stained section from treated C/L+T and C/T790M mice (right panels) (original magnification, ×40). (C) MRI images of lungs from tumor-bearing C/L+T and C/T790M mice, pretreatment, after treatment with either cetuximab for 2 weeks or BIBW-2992 for 2 weeks, and after treatment with cetuximab (cetux) and BIBW-2992 for 4 weeks. H&E-stained sections of lungs from mice treated with the drug combination (right panels) (original magnification, ×40). Representative images are shown from all studies.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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