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Review
. 2014 Sep 12;8(6):1067-83.
doi: 10.1016/j.molonc.2014.05.004. Epub 2014 May 21.

Drug resistance to targeted therapies: déjà vu all over again

Floris H Groenendijk  1 , René Bernards  2
Affiliations
Review

Drug resistance to targeted therapies: déjà vu all over again

Floris H Groenendijk et al. Mol Oncol. .

Abstract

A major limitation of targeted anticancer therapies is intrinsic or acquired resistance. This review emphasizes similarities in the mechanisms of resistance to endocrine therapies in breast cancer and those seen with the new generation of targeted cancer therapeutics. Resistance to single-agent cancer therapeutics is frequently the result of reactivation of the signaling pathway, indicating that a major limitation of targeted agents lies in their inability to fully block the cancer-relevant signaling pathway. The development of mechanism-based combinations of targeted therapies together with non-invasive molecular disease monitoring is a logical way forward to delay and ultimately overcome drug resistance development.

Keywords: Anticancer therapy; Drug combinations; Drug resistance; Endocrine therapy; Pathway reactivation; Targeted therapy.

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Figures

Figure 1
Figure 1
Schematic representation of three recurrent mechanisms of resistance to targeted therapies. RTK: receptor tyrosine kinase. STK: serine/threonine kinase. (a) Alterations of the drug target, e.g. mutation, amplification or splice variants. (b) Pathway reactivation through (1) RTK activation or (2) mutation or amplification of an upstream component or (3) by mutation or amplification of a downstream component. (c) Bypass by parallel pathway activation through (1) activation of a second RTK (by itself or through feedback regulation) or (2) mutation of a parallel STK.
Figure 2
Figure 2
Strategies to overcome intrinsic resistance and delay acquired resistance. (a) The design of more selective and potent inhibitors, also for what is currently ‘undruggable’. (b) The development of more effective drug combinations, e.g. by investigating mechanisms of drug resistance in the clinic or by in vitro and in vivo synthetic lethality screens. (c) Repeated non‐invasive detection of emerging resistance variants, for example in tumor‐derived cell‐free DNA (cfDNA), to dynamically adapt the combination strategy.
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