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Generation of drug-resistant tumors using intermittent dosing of tyrosine kinase inhibitors in mouse.

Authors
Type
Published Article
Journal
Cold Spring Harbor Protocols
1559-6095
Publisher
Cold Spring Harbor Laboratory
Publication Date
Volume
2014
Issue
2
Pages
178–181
Identifiers
DOI: 10.1101/pdb.prot077842
PMID: 24492774
Source
Medline

Abstract

Resistance to targeted therapies has emerged as a major hurdle for the successful use of drugs in the clinic. Therefore, understanding the underlying molecular mechanisms of drug resistance is crucial for the identification of strategies to prevent and overcome it. Given the defined nature of the oncogenic lesions present in genetically engineered mouse models (GEMMs) and the relative ease of sample collection and analysis, they are ideal systems in which to recapitulate the response and subsequent emergence of resistance to targeted therapies. When agents that are very effective at eradicating tumors are used in GEMMs, obtaining drug-resistant tumors can be a challenge. One approach to generating such tumors is the use of a suboptimal intermittent dosing strategy to treat the animals, which allows for periods of tumor growth and progression in the absence of drug. This intermittent dosing strategy has been used successfully to study resistance to the tyrosine kinase erlotinib in lung cancer models and is described here. Although this protocol is specific for this experimental system, the concepts and general design can be adapted for use with GEMMs of other cancers.

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