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A snapshot of chemoresistance to PARP inhibitors
1Department of Preclinical and Clinical Pharmacology, University of Florence, Viale Pieraccini 6, 50139 Firenze, Italy. alberto.chiarugi@unifi.it
Abstract:
The exploitation of synthetic lethality in BRCA-deficient tumor carriers using potent inhibitors of the enzyme poly(ADP-ribose) polymerase (PARP)-1 has led to an enthusiastic response among basic scientists, oncologists and pharmaceutical companies. However, accumulating evidence demonstrates that resistance to these drugs develops in tumors in both preclinical and clinical settings. Here, I focus on literature dealing with resistance to these drugs and discuss the molecular mechanisms involved, such as restoration of BRCA function, upregulation of nonhomologous end-joining-dependent DNA repair, induction of P-glycoprotein expression and epigenetic deregulation. Clinical implications of resistance to PARP1 inhibitors are also discussed.
Insights
Resistance to poly(ADP-ribose) polymerase (PARP) inhibitors in BRCA-deficient tumors is a growing concern. This review details molecular mechanisms driving this resistance, including DNA repair pathway alterations and drug efflux.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Synthetic lethality exploiting BRCA deficiency with poly(ADP-ribose) polymerase (PARP) inhibitors shows promise.
- Tumor resistance to PARP inhibitors is emerging in preclinical and clinical settings.
Purpose of the Study:
- To review and discuss the molecular mechanisms of resistance to PARP inhibitors.
- To explore the clinical implications of PARP inhibitor resistance.
Main Methods:
- Literature review focusing on resistance mechanisms to PARP inhibitors.
- Analysis of molecular pathways involved in acquired resistance.
Main Results:
- Key resistance mechanisms include restoration of BRCA function, upregulation of nonhomologous end-joining DNA repair, P-glycoprotein induction, and epigenetic deregulation.
- These mechanisms can counteract the effects of PARP inhibition.
Conclusions:
- Understanding resistance mechanisms is crucial for overcoming therapeutic limitations.
- Strategies to address PARP inhibitor resistance are needed to improve patient outcomes in BRCA-mutated cancers.
