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 BRCA mutations and also BRCA-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.
Highlights
Over the past decade, poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) and monoclonal antibodies that block immune checkpoints, such as programmed cell-death 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTL-4), have transformed the treatment of multiple types of cancers
In light of the evidence that unrepaired DNA damage induced by PARPi expands the anti-tumor activity of the immune checkpoint inhibitor (ICI), the therapeutic landscape of DNA damage response (DDR)-targeting agents has promptly unfolded to include inhibitors of other key mediators implied in DNA replication and repair, such as ataxia telangiectasia mutated (ATM), ataxia telengiectasia Rad3-related (ATR), Chk1, Chk2, DNA-PK, and WEE1 [166]
While in vitro studies in non-homologous recombination deficiencies (HRD) cancer cell lines provide the rationale for a combined strategy, in vivo preclinical evidence suggesting that PARPi might increase the efficacy of ICIs has been conducted preferentially in BRCA-deficient tumor models, limiting the translational relevance
Summary
Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) and monoclonal antibodies that block immune checkpoints, such as programmed cell-death 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTL-4), have transformed the treatment of multiple types of cancers. Monotherapy with PARPi as a maintenance strategy showed significant clinical activity in several cancer types harboring germline loss-of-function BRCA mutations such as ovarian, breast and pancreatic cancer [8,9,10,11]. Despite these substantial advancements in clinical care, the majority of patients receiving either PARPi or ICIs alone do not provide benefit and a rationale to combine these treatments has emerged [12,13]. We summarize the basic and translational biology supporting the combined strategy and provide a focus on preclinical studies and ongoing clinical trials of ICIs combined with PARPi, as well as perspectives and potential challenges of this combination strategy
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