Understanding and overcoming resistance to PARP inhibitors in cancer therapy

• Published in: Nature reviews. Clinical oncology Vol. 18; no. 12; pp. 773 - 791
• Main Authors: Dias, Mariana Paes, Moser, Sarah C., Ganesan, Shridar, Jonkers, Jos
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.12.2021; Nature Publishing Group
• Subjects: 631/337/1427/2566; 631/67/1059/2326; 692/4028/67/1059/2326; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; BRCA1 protein; Cancer; Cancer therapies; Care and treatment; Clinical trials; Clinical Trials as Topic; DNA repair; Drug resistance; Drug Resistance, Neoplasm - drug effects; Drug Therapy; Enzyme inhibitors; Genetic aspects; Genomic instability; Genomic Instability - drug effects; Health aspects; Homologous recombination; Humans; Medicine; Medicine & Public Health; Neoplasms - drug therapy; Neoplasms - genetics; Oncology; Patient outcomes; Patients; Poly(ADP-ribose); Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use; Prevention; Review Article; Ribose; Targeted cancer therapy; Tumors; Netherlands
• ISSN: 1759-4774; 1759-4782
• DOI: 10.1038/s41571-021-00532-x

Developing novel targeted anticancer therapies is a major goal of current research. The use of poly(ADP-ribose) polymerase (PARP) inhibitors in patients with homologous recombination-deficient tumours provides one of the best examples of a targeted therapy that has been successfully translated into the clinic. The success of this approach has so far led to the approval of four different PARP inhibitors for the treatment of several types of cancers and a total of seven different compounds are currently under clinical investigation for various indications. Clinical trials have demonstrated promising response rates among patients receiving PARP inhibitors, although the majority will inevitably develop resistance. Preclinical and clinical data have revealed multiple mechanisms of resistance and current efforts are focused on developing strategies to address this challenge. In this Review, we summarize the diverse processes underlying resistance to PARP inhibitors and discuss the potential strategies that might overcome these mechanisms such as combinations with chemotherapies, targeting the acquired vulnerabilities associated with resistance to PARP inhibitors or suppressing genomic instability. Poly(ADP-ribose) polymerase (PARP) inhibitors are approved for patients with several forms of cancer, predominantly those harbouring loss-of-function BRCA1/2 mutations or other homologous recombination defects. Nonetheless, most patients receiving PARP inhibitors will ultimately develop resistance to PARP inhibitors, resulting in disease progression. In this Review, the authors describe the mechanisms of resistance to PARP inhibitors and discuss the potential treatment strategies that might overcome these effects. Key points BRCA1/2-deficient cells are extremely vulnerable to PARP inhibition; this finding has led to the successful clinical development of PARP inhibitors for the treatment of patients with BRCA1/2 -mutant cancers. The use of PARP inhibitors is currently being expanded beyond patients with ovarian and breast cancers to those with homologous recombination-deficient tumours of other histologies such as prostate or pancreatic cancers. Resistance to PARP inhibitors occurs through three main mechanisms: drug target-related resistance, restoration of homologous recombination and restoration of replication fork stability. Current approaches to overcome resistance are focused on combining PARP inhibition with other inhibitors of the DNA damage response, immune-checkpoint inhibition or targeted therapies. Targeting the acquired vulnerabilities of PARP inhibitor-resistant tumours might selectively kill unresponsive cancer cells. Preventing the development of genomic instability in DNA repair-deficient cancers by inhibiting the activity of the error-prone polymerase POLθ might be a promising strategy to target a known vulnerability of these tumours.