Homologous Recombination Repair Deficiency: History
Subjects: Cell Biology
Contributors:

Homologous recombination repair deficiency (HRD) can be observed in virtually all cancer
types. Although HRD sensitizes tumors to DNA-damaging chemotherapy and poly(ADP-ribose)
polymerase (PARP) inhibitors, all patients ultimately develop resistance to these therapies. Therefore,
it is necessary to identify therapeutic regimens with a more durable efficacy. HRD tumors have been
suggested to be more immunogenic and, therefore, more susceptible to treatment with checkpoint
inhibitors. In this review, we describe how HRD might mechanistically affect antitumor immunity
and summarize the available translational evidence for an association between HRD and antitumor
immunity across multiple tumor types. In addition, we give an overview of all available clinical data
on the efficacy of checkpoint inhibitors in HRD tumors and describe the evidence for using treatment
strategies that combine checkpoint inhibitors with PARP inhibitors.

  • cancer
  • homologous recombination repair deficiency
  • immune checkpoint inhibitors

Introduction

Cells possess a complex set of non-redundant and partially overlapping pathways to detect and repair DNA damage, including base modifications, strand breaks, and interstrand crosslinks. Major DNA damage repair (DDR) pathways include direct repair, base excision repair, nucleotide excision repair, mismatch repair (MMR), homologous recombination (HR), non-homologous end joining (NHEJ), and the Fanconi anemia repair pathway, with each of these pathways directed at specific types of DNA damage [1].
In cancer, DDR is frequently disrupted, leading to genomic instability. One of the pathways that is regularly altered in cancer is HR. HR is an important pathway for the repair of double-strand DNA breaks (DSBs) during the S and G2 phase of the cell cycle, i.e., after DNA replication has occurred. HR is considered a relatively error-free process because it uses an intact sister chromatid to guide DNA repair. HR deficiency (HRD) leads to enhanced reliance on alternative pathways involved in DSB repair, i.e., classical NHEJ, alternative end joining, and single-strand annealing [2,3]. These pathways repair DSBs without a homologous DNA template, resulting in characteristic genomic scars across the genome [4,5].
Two well-known genes that play an important role in HR are BRCA1 and BRCA2. Germline pathogenic BRCA variants have long been recognized for their role in cancer susceptibility, increasing the risk of breast, ovarian, prostate, and pancreatic cancers [6,7]. Nevertheless, BRCA mutations can also arise in tumors of patients without pathogenic germline variants. Deleterious variants in BRCA1 or BRCA2, either germline or somatic, are most frequently observed in ovarian cancer (13.8%), castrate-resistant prostate cancer (11.8%), and breast cancer (6.8%), but can occur in many other cancer types as well [8,9]. In addition to BRCA1 and BRCA2, many other genes play a direct or indirect role in HR. Nevertheless, the exact implications of aberrations in other HR-related genes for the functionality of the HR pathway are largely unclear [10].
HRD tumors respond differently to anti-neoplastic agents as compared to non-HRD tumors. BRCA-mutated ovarian, breast, and prostate cancers have been described to be more sensitive to DNA-damaging chemotherapy, i.e., platinum chemotherapy [11,12,13], or poly(ADP-ribose) polymerase (PARP) inhibitors [9,14,15]. Nevertheless, patients ultimately develop resistance to these therapies. There is a need for more effective and durable treatment strategies.
In the last decade, immune checkpoint inhibitors have been registered for the treatment of several cancer types. Currently approved agents target programmed cell death protein 1 (PD-1), its ligand PD-L1, or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). While checkpoint inhibitors induce responses and improve overall survival (OS) in various types of cancers, a long-term benefit is observed in only a minority of patients. At present, it is largely unclear which patients will benefit from it. A role for DDR defects in selecting patients for immunotherapy has been suggested. MMR-deficient tumors, which are characterized by a hypermutated genome and instability of DNA repeat regions, have been shown to be responsive to checkpoint inhibitors, independent of tumor type [16]. Other DDR defects, particularly those leading to HRD, may also render tumors more susceptible for checkpoint inhibitors.
The first part of this review describes how HRD might mechanistically affect antitumor immunity. In the second part, the current evidence for an association between HRD and tumor-infiltrating immune cells is summarized and an overview is given of available clinical data on the efficacy of checkpoint inhibitors in HRD tumors. We focus on tumors with BRCA inactivation, as the functional implications of other HR-related genes remain uncertain and studies considering genome-wide HRD signatures are scarce. Finally, we describe the evidence for synergism between checkpoint inhibitors and PARP inhibitors in BRCA-inactivated tumors.

This entry is adapted from the peer-reviewed paper 10.3390/cancers13092249