Development of New Mouse Lung Tumor Models Expressing EGFR T790M Mutants Associated with Clinical Resistance to Kinase Inhibitors

Lucia Regales,David B Solit,Maureen F Zakowski,Jason A Koutcher,Carl Le,William Pao,Marissa N Balak,Ayana Sawai,Neal Rosen,Katerina Politi,Yixuan Gong,Ming You

doi:10.1371/journal.pone.0000810

Lucia Regales, David B Solit + Show 10 more

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https://doi.org/10.1371/journal.pone.0000810

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Abstract

BackgroundThe EGFR T790M mutation confers acquired resistance to kinase inhibitors in human EGFR mutant lung adenocarcinoma, is occasionally detected before treatment, and may confer genetic susceptibility to lung cancer.Methodology/Principal FindingsTo study further its role in lung tumorigenesis, we developed mice with inducible expression in type II pneumocytes of EGFRT790M alone or together with a drug-sensitive L858R mutation. Both transgenic lines develop lung adenocarcinomas that require mutant EGFR for tumor maintenance but are resistant to an EGFR kinase inhibitor. EGFRL858R+T790M-driven tumors are transiently targeted by hsp90 inhibition. Notably, EGFRT790M-expressing animals develop tumors with longer latency than EGFRL858R+T790M-bearing mice and in the absence of additional kinase domain mutations.Conclusions/SignificanceThese new mouse models of mutant EGFR-dependent lung adenocarcinomas provide insight into clinical observations. The models should also be useful for developing improved therapies for patients with lung cancers harboring EGFRT790M alone or in conjunction with drug-sensitive EGFR kinase domain mutations.

Highlights

Point mutations in the kinase domain of mutant epidermal growth factor receptors (EGFRs) are associated with acquired resistance to the EGFR inhibitors, gefitinib (Iressa) and erlotinib (Tarceva) in human lung adenocarcinoma [1,2,3,4,5]
We first generated a double mutant EGFR allele encoding the T790M mutation associated with EGFR kinase inhibitor resistance together with the L858R mutation associated with drug sensitivity (Figure 1)
Transgene expression was induced in weaned double transgenic progeny by administering dox via the animal diet [16]

Summary

Introduction

Point mutations in the kinase domain of mutant epidermal growth factor receptors (EGFRs) are associated with acquired resistance to the EGFR inhibitors, gefitinib (Iressa) and erlotinib (Tarceva) in human lung adenocarcinoma [1,2,3,4,5]. Identified in the context of drug resistance, emerging data suggest that the T790M change may potentiate oncogenic activity, either by itself or in association with alterations in the EGFR kinase domain already known to confer gain-of-function properties [7,8,9] Such alterations include deletions in exon 19 and point mutations in exon 21 (L858R). To study further its role in lung tumorigenesis, we developed mice with inducible expression in type II pneumocytes of EGFRT790M alone or together with a drug-sensitive L858R mutation Both transgenic lines develop lung adenocarcinomas that require mutant EGFR for tumor maintenance but are resistant to an EGFR kinase inhibitor. The models should be useful for developing improved therapies for patients with lung cancers harboring EGFRT790M alone or in conjunction with drug-sensitive EGFR kinase domain mutations

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