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Nat Rev Clin Oncol. 2016 Jun;13(6):335-47. doi: 10.1038/nrclinonc.2015.175. Epub 2015 Oct 20.

The influence of subclonal resistance mutations on targeted cancer therapy.

Schmitt MW1,2,3, Loeb LA1, Salk JJ1,2,3.

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Departments of Biochemistry and Pathology, University of Washington, 1959 Northeast Pacific Street, Box 357705, Seattle, WA 98195, USA.
Division of Medical Oncology, Department of Medicine, University of Washington, 1959 Northeast Pacific Street, Box 357705, Seattle, WA 98195, USA.
Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Box 19024, Seattle, WA 98109, USA.


Clinical oncology is being revolutionized by the increasing use of molecularly targeted therapies. This paradigm holds great promise for improving cancer treatment; however, allocating specific therapies to the patients who are most likely to derive a durable benefit continues to represent a considerable challenge. Evidence continues to emerge that cancers are characterized by extensive intratumour genetic heterogeneity, and that patients being considered for treatment with a targeted agent might, therefore, already possess resistance to the drug in a minority of cells. Indeed, multiple examples of pre-existing subclonal resistance mutations to various molecularly targeted agents have been described, which we review herein. Early detection of pre-existing or emerging drug resistance could enable more personalized use of targeted cancer therapy, as patients could be stratified to receive the therapies that are most likely to be effective. We consider how monitoring of drug resistance could be incorporated into clinical practice to optimize the use of targeted therapies in individual patients.

[Indexed for MEDLINE]
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