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Combined PARP Inhibition and Immune Checkpoint Therapy in Solid Tumors. | LitMetric

Combined PARP Inhibition and Immune Checkpoint Therapy in Solid Tumors.

Cancers (Basel)

Department of Medical Oncology, Institut Bergonié, 33000 Bordeaux, France.

Published: June 2020

AI Article Synopsis

  • Genomic instability in cancers from DNA damage response deficiencies can be targeted with therapies like PARP inhibitors, which disrupt DNA repair in tumors with existing defects, leading to synthetic lethality.
  • PARP inhibitors show effectiveness across various cancers, particularly those with homologous recombination deficiencies (HRD), while immune checkpoint inhibitors (ICIs) boost anti-tumor effects in diverse cancer types based on the immune environment.
  • Combining PARP inhibitors with ICIs may enhance treatment response by modulating the tumor immune microenvironment, with early trials suggesting synergistic effects, although challenges and future directions for this combination strategy are also discussed.

Article Abstract

Genomic instability is a hallmark of cancer related to DNA damage response (DDR) deficiencies, offering vulnerabilities for targeted treatment. Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) interfere with the efficient repair of DNA damage, particularly in tumors with existing defects in DNA repair, and induce synthetic lethality. PARPi are active across a range of tumor types harboring mutations and also -negative cancers, such as ovarian, breast or prostate cancers with homologous recombination deficiencies (HRD). Depending on immune contexture, immune checkpoint inhibitors (ICIs), such as anti-PD1/PD-L1 and anti-CTLA-4, elicit potent antitumor effects and have been approved in various cancers types. Although major breakthroughs have been performed with either PARPi or ICIs alone in multiple cancers, primary or acquired resistance often leads to tumor escape. PARPi-mediated unrepaired DNA damages modulate the tumor immune microenvironment by a range of molecular and cellular mechanisms, such as increasing genomic instability, immune pathway activation, and PD-L1 expression on cancer cells, which might promote responsiveness to ICIs. In this context, PARPi and ICIs represent a rational combination. In this review, we summarize the basic and translational biology supporting the combined strategy. We also detail preclinical results and early data of ongoing clinical trials indicating the synergistic effect of PARPi and ICIs. Moreover, we discuss the limitations and the future direction of the combination.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352466PMC
http://dx.doi.org/10.3390/cancers12061502DOI Listing

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