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.

Fig. 1

Summary of RTKs known to mediate bypass resistance to RTK targeted cancer therapy. Ovals indicate oncogenes responsible for initial tumor formation and rectangles indicate RTKs involved in drug resistance. Arrows denote known bypass resistance mechanisms. Note that EGFR and HER2 activation can induce initial tumor formation and also mediate resistance.