The influence of subclonal resistance mutations on targeted cancer therapy
Michael W Schmitt1,2,3, Lawrence A Loeb1, Jesse J Salk1,2,3
1Departments of Biochemistry and Pathology, University of Washington, 1959 Northeast Pacific Street, Box 357705, Seattle, WA 98195, USA.
Abstract:
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.
Insights
Molecularly targeted therapies offer promise in cancer treatment, but drug resistance poses a challenge. Early detection of resistance can personalize therapy for better patient outcomes.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Molecularly targeted therapies are transforming cancer treatment.
- Patient selection for targeted therapies remains a challenge due to tumor heterogeneity.
- Pre-existing or emerging drug resistance can limit treatment efficacy.
Purpose of the Study:
- To review examples of pre-existing subclonal resistance mutations.
- To discuss the implications of intratumour genetic heterogeneity for targeted therapy.
- To explore strategies for monitoring drug resistance in clinical practice.
Main Methods:
- Literature review of pre-existing resistance mutations.
- Analysis of intratumour genetic heterogeneity.
- Discussion of clinical monitoring strategies for drug resistance.
Main Results:
- Multiple instances of pre-existing subclonal resistance mutations to targeted agents have been identified.
- Intratumour genetic heterogeneity can lead to inherent drug resistance in a subset of cancer cells.
- Monitoring for drug resistance could facilitate personalized treatment approaches.
Conclusions:
- Early detection of drug resistance is crucial for optimizing targeted cancer therapy.
- Personalized medicine approaches require stratification of patients based on resistance profiles.
- Integrating drug resistance monitoring into clinical practice can improve patient outcomes.
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