Optimizing poly (ADP‐ribose) polymerase inhibition through combined epigenetic and immunotherapy

• Published in: Cancer science Vol. 109; no. 11; pp. 3383 - 3392
• Main Authors: Prasanna, Thiru, Wu, Fan, Khanna, Kum Kum, Yip, Desmond, Malik, Laeeq, Dahlstrom, Jane E., Rao, Sudha
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01-11-2018; John Wiley and Sons Inc
• Subjects: Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Antineoplastic drugs; Antitumor agents; Apoptosis; B7-H1 Antigen - genetics; Breast cancer; cancer stem cell; Cancer therapies; Cell cycle; Cell death; Chemotherapy; Clinical Trials as Topic; Cytotoxicity; Deoxyribonucleic acid; DNA; DNA damage; DNA repair; Drug Resistance, Neoplasm - drug effects; Drugs; Epidermal growth factor; Epigenesis, Genetic - drug effects; Epigenetics; Female; Gene Expression Regulation, Neoplastic - drug effects; Histone deacetylase; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylase Inhibitors - therapeutic use; Homologous recombination; Homologous Recombination - drug effects; Humans; immune checkpoint inhibitor; Immunogenicity; Immunosuppressive agents; Immunotherapy; Ligands; Lysine; lysine‐specific histone demethylase‐1A; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Ovarian cancer; PD-1 protein; PD-L1 protein; Phenotypes; poly (ADP‐ribose) polymerase inhibitor; Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use; Proteins; Response rates; Review; Ribose; Stem cells; Transcription factors; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - metabolism; triple‐negative breast cancer; Tumors; Up-Regulation - drug effects; immune checkpoint inhibitor; triple-negative breast cancer; cancer stem cell; lysine-specific histone demethylase-1A; poly (ADP-ribose) polymerase inhibitor
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.13799

Triple‐negative breast cancer (TNBC) is an aggressive breast cancer subtype with poor survival outcomes. Currently, there are no targeted therapies available for TNBCs despite remarkable progress in targeted and immune‐directed therapies for other solid organ malignancies. Poly (ADP‐ribose) polymerase inhibitors (PARPi) are effective anticancer drugs that produce good initial clinical responses, especially in homologous recombination DNA repair‐deficient cancers. However, resistance is the rule rather than the exception, and recurrent tumors tend to have an aggressive phenotype associated with poor survival. Many efforts have been made to overcome PARPi resistance, mostly by targeting genes and effector proteins participating in homologous recombination that are overexpressed during PARPi therapy. Due to many known and unknown compensatory pathways, genes, and effector proteins, overlap and shared resistance are common. Overexpression of programmed cell death‐ligand 1 (PD‐L1) and cancer stem cell (CSC) sparing are novel PARPi resistance hypotheses. Although adding programmed cell death‐1 (PD‐1)/PD‐L1 inhibitors to PARPi might improve immunogenic cell death and be crucial for durable responses, they are less likely to target the CSC population that drives recurrent tumor growth. Lysine‐specific histone demethylase‐1A and histone deacetylase inhibitors have shown promising activity against CSCs. Combining epigenetic drugs such as lysine‐specific histone demethylase‐1A inhibitors or histone deacetylase inhibitors with PARPi/anti‐PD‐1/PD‐L1 is a novel, potentially synergistic strategy for priming tumors and overcoming resistance. Furthermore, such an approach could pave the way for the identification of new upstream epigenetic and genetic signatures.
Poly (ADP‐ribose) polymerase inhibitors are effective anticancer drugs that produce good initial clinical response. However, resistance is the rule rather than the exception, and recurrent tumors tend to have an aggressive phenotype associated with poor survival. Addition of epigenetic drugs and checkpoint inhibitors is a novel, potentially synergistic strategy for priming tumors and overcoming PARP inhibitor resistance.