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Published on: September 19, 2019
Genetic heterogeneity and cancer drug resistance
Nicholas C Turner1, Jorge S Reis-Filho
1Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK.
Abstract:
Despite the success of targeted therapies in the treatment of cancer, the development of resistance limits the ability to translate this method into a curative treatment. The mechanisms of resistance have traditionally been thought of as intrinsic (ie, present at baseline) or acquired (ie, developed after initial response). Recent evidence has challenged the notion of acquired resistance. Although cancers are traditionally thought to be clonal, there is now evidence of intra-tumour genetic heterogeneity in most cancers. The clinical pattern of acquired resistance in many circumstances represents outgrowth of resistant clones that might have originally been present in the primary cancer at low frequency but that have expanded under the selective pressure imposed by targeted therapies. Here, we describe the potential role of clonal heterogeneity in resistance to targeted therapy, discuss genetic instability as one of its causes, and detail approaches to tackle intra-tumour heterogeneity in the clinic.
Insights
Cancer treatment resistance is often due to pre-existing resistant clones within a tumor, not acquired resistance. Understanding intra-tumor genetic heterogeneity is key to overcoming targeted therapy limitations.
Area of Science:
- Oncology
- Cancer Biology
- Genetics
Background:
- Targeted therapies have improved cancer treatment but are limited by resistance.
- Resistance mechanisms were traditionally classified as intrinsic or acquired.
- Recent findings challenge the concept of acquired resistance in cancer.
Purpose of the Study:
- To explore the role of clonal heterogeneity in resistance to targeted cancer therapy.
- To discuss genetic instability as a driver of intra-tumor heterogeneity.
- To outline clinical strategies for addressing intra-tumor heterogeneity.
Main Methods:
- Review of recent evidence on cancer treatment resistance.
- Analysis of the concept of intra-tumor genetic heterogeneity.
- Discussion of clinical approaches to manage tumor heterogeneity.
Main Results:
- Intra-tumor genetic heterogeneity is prevalent in most cancers.
- Apparent acquired resistance often results from the expansion of pre-existing resistant clones under therapy pressure.
- Genetic instability contributes to the development of tumor heterogeneity.
Conclusions:
- Intra-tumor heterogeneity, driven by factors like genetic instability, plays a critical role in targeted therapy resistance.
- Rethinking resistance mechanisms from acquired to outgrowth of pre-existing clones is essential.
- Developing strategies to target intra-tumor heterogeneity is crucial for improving cancer treatment outcomes.
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