Resistance to receptor tyrosine kinase inhibition in cancer: molecular mechanisms and therapeutic strategies

Abstract

Drug resistance is a major factor that limits the efficacy of targeted cancer therapies. In this review, we discuss the main known mechanisms of resistance to receptor tyrosine kinase inhibitors, which are the most prevalent class of targeted therapeutic agent in current clinical use. Here we focus on bypass track resistance, which involves the activation of alternate signaling molecules by tumor cells to bypass inhibition and maintain signaling output, and consider the problems of signaling pathway redundancy and how the activation of different receptor tyrosine kinases translates into intracellular signal transduction in different cancer types. This information is presented in the context of research strategies for the discovery of new targets for pharmacological intervention, with the goal of overcoming resistance in order to improve patient outcomes.

Keywords

targeted therapy / drug resistance / receptor tyrosine kinases / cancer

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Acknowledgements

This study was supported by National Institutes of Health Grants CA186800 (X.F.W.) and CA059365 (P.B.A.).

Compliance with ethics guidelines

Peter B. Alexander and Xiao-Fan Wang declare that they have no conflict of interest. This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

RIGHTS & PERMISSIONS

2014 Higher Education Press and Springer-Verlag Berlin Heidelberg