Poly (ADP-ribose) polymerase inhibitors (PARPi) for advanced malignancies with multiple DNA-repair genetic aberrations

ABSTRACT

Introduction

Poly (ADP-ribose) polymerase inhibitors (PARPi) have been approved for the treatment of advanced tumors with defects in genes involved in homologous recombination repair (HRR), including cancers of the prostate, pancreas, breast, and ovary. In these advanced tumors, PARPi afford ‘synthetic lethality’ by blocking the PARP-associated repair pathway in cancer cells with HRR genetic mutations, resulting in chromosome instability and cellular apoptosis. According to the synthetic lethality theory, patients with a greater burden of genetic alterations, in proportion (relative quantity) or category, would have more satisfactory outcomes after PARPi administration. However, this issue remains obscure based on the existing sporadic evidence.

Areas covered

We summarize the therapeutic effects of PARPi in advanced tumors with multiple HRR genetic mutations, and attempted to compare these results with those obtained for cancers with a single mutation.

Expert opinion

Limited evidence has provided a possibly encouraging response to PARPi among patients carrying multiple HRR genetic mutations compared with those with a single mutation (although the treatment effect was negative in some patients). Further research is needed to understand the role of PARPi in tumor cells with multiple HRR genetic mutations.

KEYWORDS:

• PARPi
• genetic mutation
• homologous recombination repair
• DNA damage repair
• cancer treatment

Article highlights

• The PARPi is synthetic lethal in advanced cancers with a deficiency in DNA repair. Patients with advanced tumor with multiple HRR genetic mutations should be more concentrated.

• The interactions between different HRR genetic mutations in advance cancers may affect the outcomes of PARPi administration.

• Sporadic existing evidence revealed that encouraging responses to PARPi for advanced tumors with multiple HRR genetic mutations, although responses was negative in some patients.

• Some limitations in current literature should be carefully explained, which would largely affect the results and popularizing of PARPi administration.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Supplementary material

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Additional information

Funding

This work was supported by the Innovation Program for Chongqing’s Overseas Returnees (cx2019146); High-level Medical Reserved Personnel Training Project of Chongqing (the 4th batch) ; and Research Program of Basic Science and Frontier Technology in Chongqing (cstc2017jcyjAX0435).