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

Thiruvarudsothy PRASANNA, Fan Wu, Kum Kum Khanna, Desmond Yip, Laeeq Malik, Jane E. Dahlstrom, Sudha Rao

Research output: Contribution to journalReview article

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Abstract

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.

Original languageEnglish
Pages (from-to)3383-3392
Number of pages10
JournalCancer Science
Volume109
Issue number11
DOIs
Publication statusPublished - 1 Nov 2018

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Poly(ADP-ribose) Polymerases
Epigenomics
Immunotherapy
CD274 Antigen
Cell Death
Histone Demethylases
Histone Deacetylase Inhibitors
Neoplastic Stem Cells
Neoplasms
Triple Negative Breast Neoplasms
Recombinational DNA Repair
Poly(ADP-ribose) Polymerase Inhibitors
Homologous Recombination
Pharmaceutical Preparations
Proteins
Therapeutics
Breast Neoplasms
Ligands
Phenotype
Growth

Cite this

PRASANNA, Thiruvarudsothy ; Wu, Fan ; Khanna, Kum Kum ; Yip, Desmond ; Malik, Laeeq ; Dahlstrom, Jane E. ; Rao, Sudha. / Optimizing poly (ADP-ribose) polymerase inhibition through combined epigenetic and immunotherapy. In: Cancer Science. 2018 ; Vol. 109, No. 11. pp. 3383-3392.
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abstract = "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.",
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Optimizing poly (ADP-ribose) polymerase inhibition through combined epigenetic and immunotherapy. / PRASANNA, Thiruvarudsothy; Wu, Fan; Khanna, Kum Kum; Yip, Desmond; Malik, Laeeq; Dahlstrom, Jane E.; Rao, Sudha.

In: Cancer Science, Vol. 109, No. 11, 01.11.2018, p. 3383-3392.

Research output: Contribution to journalReview article

TY - JOUR

T1 - Optimizing poly (ADP-ribose) polymerase inhibition through combined epigenetic and immunotherapy

AU - PRASANNA, Thiruvarudsothy

AU - Wu, Fan

AU - Khanna, Kum Kum

AU - Yip, Desmond

AU - Malik, Laeeq

AU - Dahlstrom, Jane E.

AU - Rao, Sudha

PY - 2018/11/1

Y1 - 2018/11/1

N2 - 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.

AB - 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.

KW - cancer stem cell

KW - immune checkpoint inhibitor

KW - lysine-specific histone demethylase-1A

KW - poly (ADP-ribose) polymerase inhibitor

KW - triple-negative breast cancer

UR - http://www.scopus.com/inward/record.url?scp=85055249301&partnerID=8YFLogxK

U2 - 10.1111/cas.13799

DO - 10.1111/cas.13799

M3 - Review article

VL - 109

SP - 3383

EP - 3392

JO - Japanese Journal of Cancer Research

JF - Japanese Journal of Cancer Research

SN - 1347-9032

IS - 11

ER -