Chinese Medical Journal article reveals the anticancer potential of poly ADP-ribose polymerase inhibitors

Cancer, characterized by the development of abnormal cells that divide uncontrollably, is generally associated with significant disease burden and high death rates. However, advancements in cancer biology, diagnostics, and therapeutics have greatly improved the treatment outcomes of patients with cancer. In recent years, targeted anticancer therapies such as poly adenosine diphosphate-ribose polymerase (PARP) inhibitors have gained the attention of researchers across the globe.

PARP enzymes play a key role in repair of DNA and maintenance of genomic stability. While PARP activity is critical for the survival and effective functioning of normal cells, inhibiting PARPs in cancer cells with mutations or genetic damage induced by chemotherapy can be beneficial. To evaluate the current status of PARPis in cancer therapy and investigate the anticancer potential of PARPis against different types of cancers, a team of researchers led by Dr. Yujun Shi from the Department of Pathology and Institute of Clinical Pathology, Sichuan University, China have conducted a comprehensive review of literature. Their research findings were published online in the Chinese Medical Journal on 11 February 2025.

In the initial part of their study, Dr. Shi and his team provide an in-depth analysis of PARPs in DNA repair mechanisms. PARPs have the ability to recognize single-strand break (SSB) in DNA and recruit vital repair proteins by synthesizing poly adenosine diphosphate-ribose (PAR) chains. In addition to SSB repair of DNA, PARP aids the repair of double-strand breaks (DSBs) via homologous recombination repair (HRR) and nonhomologous end-joining (NHEJ) repair pathways. Inhibition of PARP activity, especially in cancer cells with breast cancer susceptibility gene (BRCA)1 and BRCA2 mutations, leads to accumulation of SSBs that subsequently transform into DSBs, and ultimately results in cell death.

Explaining the remarkable efficacy of PARPis in treating cancers with BRCA1/2 mutations, Dr. Shi shares, “Mutations in BRCA1/2 lead to the loss of HRR functionality, severely compromising the ability of cancer cells to repair DNA damage. Consequently, these cancer cells rely on alternative repair pathways, such as base excision repair (BER), to preserve their genomic integrity. PARPis block the BER pathway, preventing DNA repair in HRR-deficient cancer cells and leading to cell death. This phenomenon, called “synthetic lethality,” underpins the rationale for employing PARPis in cancer therapy”.

Furthermore, the researchers delve into the molecular dynamics of PARPis and outline the use of diverse chemical groups like thiazole and tetrahydroquinazoline in enhancing the selectivity and potency of PARPis. Notably, PARPis such as olaparib, niraparib, and rucaparib, have been clinically approved for use as standalone therapies or in combination with chemotherapy regimens. Besides gaining Food and Drug Administration (FDA) approval for treating ovarian, prostate, breast, and pancreatic cancer, PARPis have shown promising anticancer activity against gastric and lung cancer in several preclinical and clinical studies; however, they are not yet FDA-approved for these indications.

Additionally, Dr. Shi and the research team emphasize the clinical utility and safety of PARPis by describing the common adverse effects that manifest during treatment, including fatigue, nausea, mild to moderate anemia, and neutropenia. Challenges to PARPi therapy include the development of resistance via drug efflux mechanisms, PARP1 mutations, replication fork protection—where certain proteins safeguard the replication fork and prevent DNA damage—and restoration of HRR.

Interestingly, combination of PARPis with chemotherapeutic drugs can improve the overall anticancer treatment efficacy. Elaborating on the benefits of using combination therapies with PARPis, Dr. Shi says, “Notably, the use of olaparib in conjunction with platinum-based drugs, such as cispla­tin or carboplatin, has demonstrated significant efficacy in the treatment of ovarian and breast cancers. This combination strategy increases DNA damage and blocks the repair process, thereby improving treatment response rates and extending progression-free survival (PFS)”. Synergistic anticancer activity of PARPis with other cancer drugs like gemcitabine, cetuximab-monoclonal antibody, and vascular endothe­lial growth factor receptor (VEGFR) inhibitors have the potential to be developed as targeted anticancer therapies.

Overall, this study underscores the importance of PARPis in cancer therapy, especially for BRCA-mutated cancers.

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Reference

Titles of original papers: Poly(ADP-ribose) polymerase inhibitors in cancer therapy

Journal: Chinese Medical Journal

DOI: 10.1097/CM9.0000000000003471