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Immunofluorescence Imaging of DNA Damage and Repair Foci in Human Colon Cancer Cells
Published on: June 9, 2020
Biomarkers of Response and Resistance to DNA Repair Targeted Therapies
Elizabeth H Stover1, Panagiotis A Konstantinopoulos1, Ursula A Matulonis1
1Dana-Farber Cancer Institute, Boston, Massachusetts.
Abstract:
Drugs targeting DNA damage repair (DDR) pathways are exciting new agents in cancer therapy. Many of these drugs exhibit synthetic lethality with defects in DNA repair in cancer cells. For example, ovarian cancers with impaired homologous recombination DNA repair show increased sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. Understanding the activity of different DNA repair pathways in individual tumors, and the correlations between DNA repair function and drug response, will be critical to patient selection for DNA repair targeted agents. Genomic and functional assays of DNA repair pathway activity are being investigated as potential biomarkers of response to targeted therapies. Furthermore, alterations in DNA repair function generate resistance to DNA repair targeted agents, and DNA repair states may predict intrinsic or acquired drug resistance. In this review, we provide an overview of DNA repair targeted agents currently in clinical trials and the emerging biomarkers of response and resistance to these agents: genetic and genomic analysis of DDR pathways, genomic signatures of mutational processes, expression of DNA repair proteins, and functional assays for DNA repair capacity. We review biomarkers that may predict response to selected DNA repair targeted agents, including PARP inhibitors, inhibitors of the DNA damage sensors ATM and ATR, and inhibitors of nonhomologous end joining. Finally, we introduce emerging categories of drugs targeting DDR and new strategies for integrating DNA repair targeted therapies into clinical practice, including combination regimens. Generating and validating robust biomarkers will optimize the efficacy of DNA repair targeted therapies and maximize their impact on cancer treatment. Clin Cancer Res; 22(23); 5651-60. ©2016 AACR.
Insights
Targeting DNA damage repair (DDR) pathways offers new cancer therapies. Biomarkers are crucial for selecting patients and predicting response to DDR-targeted agents like PARP inhibitors.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- DNA damage repair (DDR) pathways are critical for maintaining genomic stability.
- Defects in DDR pathways can lead to cancer development and influence drug sensitivity.
- Targeting DDR pathways presents a promising strategy for cancer therapy, often exploiting synthetic lethality.
Purpose of the Study:
- To review current DNA damage repair targeted agents in clinical trials.
- To discuss emerging biomarkers for predicting response and resistance to these therapies.
- To explore new strategies for integrating DDR-targeted therapies into clinical practice.
Main Methods:
- Review of existing literature on DDR pathways and targeted agents.
- Analysis of genetic and genomic biomarkers, including mutational signatures and protein expression.
- Evaluation of functional assays for DNA repair capacity.
- Discussion of biomarkers for specific agents like PARP, ATM, ATR, and NHEJ inhibitors.
Main Results:
- Synthetic lethality is a key principle for DDR-targeted cancer therapy.
- Various biomarkers, including genomic alterations and functional assays, are being investigated for patient selection.
- Altered DNA repair function can lead to both sensitivity and resistance to DDR-targeted drugs.
- PARP inhibitors demonstrate efficacy in cancers with homologous recombination defects.
Conclusions:
- Robust biomarker development is essential for optimizing the efficacy of DNA damage repair targeted therapies.
- Understanding DDR pathway status in tumors is critical for patient stratification.
- Combination regimens and novel DDR-targeting strategies are emerging for improved cancer treatment outcomes.
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