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Cancer Sci. 2018 Sep 19. doi: 10.1111/cas.13799. [Epub ahead of print]

Optimizing PARP inhibition through combined epigenetic and immunotherapy.

Author information

1
Health Research Institute, Faculty of ESTeM, University of Canberra, Bruce, ACT, 2617, Australia.
2
Department of Medical Oncology, The Canberra Hospital, Garran, ACT, 2605, Australia.
3
QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, QLD, 4006, Australia.
4
ANU Medical School, Australian National University, Acton, ACT, 2601, Australia.
5
Department of Anatomical Pathology, ACT Pathology, The Canberra Hospital, Garran, ACT, 2605, Australia.

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 (HR) 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 HR 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 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 may 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 (LSD1) and histone deacetylase (HDAC) inhibitors have shown promising activity against CSCs. Combining epigenetic drugs such as LSD1 inhibitors or HDAC inhibitors with PARPi/anti-PD-1/PD-L1 is a novel, potentially synergistic strategy for priming tumors and overcoming resistance. Furthermore, such an approach may pave the way for the identification of new upstream epigenetic and genetic signatures. This article is protected by copyright. All rights reserved.

KEYWORDS:

Cancer stem cells; LSD1; PARP inhibitors; PD1; epigenetic drugs; immune checkpoint inhibitors; triple-negative breast cancer

PMID:
30230653
DOI:
10.1111/cas.13799
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