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Updated: Jun 16, 2025
Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms
Published on: December 9, 2015
Strategies for the prevention or reversal of PARP inhibitor resistance
Zahi Mitri1, Shaun M Goodyear2, Gordon Mills2
1Faculty of Medicine, The University of British Columbia, Vancouver, BC, Canada.
Introduction:
Advances in our understanding of tumor biology shed light on hallmarks of cancer development and progression that include dysregulated DNA damage repair (DDR) machinery. Leveraging the underlying tumor genomic instability and tumor-specific defects in DDR, Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) induced DNA damage emerges as a novel non-chemotherapy therapeutic opportunity. PARPis are currently approved in multiple tumor types, with the largest benefit seen in tumors with homologous recombination repair (HRR) deficiency, including germline and somatic mutations in BRCA1/2 genes (BRCA) and other pathway members such as PALB2 and Rad51c.
Areas Covered:
This review article summarizes the current approval landscape and known and proposed mechanisms of resistance to PARPi. Further, therapeutic strategies to overcome PARPi resistance are discussed, including ongoing clinical trials.
Expert Opinion:
PARPi have proven to be a safe and effective therapy and represents a cornerstone treatment across multiple solid tumor types. Elucidating innate and acquired mechanisms of resistance, coupled with the emergence of novel therapeutic options to capitalize on the activity of PARPi and prevent or reverse the acquisition of resistance, provides an opportunity to further expand the role of PARPi in cancer therapy.
Insights
Poly (ADP-ribose) polymerase (PARP) inhibitors are effective cancer therapies, especially in tumors with DNA damage repair deficiencies. Understanding and overcoming resistance mechanisms is key to expanding their use in oncology.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Cancer development involves dysregulated DNA damage repair (DDR) pathways.
- Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) exploit tumor genomic instability and DDR defects for therapeutic benefit.
- PARPi are approved for multiple tumor types, particularly those with homologous recombination repair (HRR) deficiency, such as BRCA-mutated cancers.
Purpose of the Study:
- To review the current approval status of PARPi.
- To summarize known and proposed mechanisms of resistance to PARPi.
- To discuss therapeutic strategies for overcoming PARPi resistance, including ongoing clinical trials.
Main Methods:
- Literature review of current approvals and resistance mechanisms.
- Analysis of proposed therapeutic strategies to overcome resistance.
- Summary of ongoing clinical trials investigating PARPi resistance.
Main Results:
- PARPi are a safe and effective cornerstone therapy in various solid tumors.
- Innate and acquired resistance mechanisms to PARPi have been elucidated.
- Novel therapeutic options are emerging to enhance PARPi activity and manage resistance.
Conclusions:
- Understanding resistance is crucial for expanding PARPi's role in cancer therapy.
- Developing strategies to prevent or reverse resistance will broaden PARPi applications.
- Further research and clinical trials are needed to optimize PARPi-based treatments.
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