Abstract
Technological breakthroughs in genomics have had a significant impact on clinical therapy for human diseases, allowing us to use patient genetic differences to guide medical care. The “synthetic lethal approach” leverages on cancer-specific genetic rewiring to deliver a therapeutic regimen that preferentially targets malignant cells while sparing normal cells. The utility of this system is evident in several recent studies, particularly in poor prognosis cancers with loss-of-function mutations that become “treatable” when two otherwise discrete and unrelated genes are targeted simultaneously. This review focuses on the chemotherapeutic targeting of epigenetic alterations in cancer cells and consolidates a network that outlines the interplay between epigenetic and genetic regulators in DNA damage repair. This network consists of numerous synergistically acting relationships that are druggable, even in recalcitrant triple-negative breast cancer. This collective knowledge points to the dawn of a new era of personalized medicine.
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Abbreviations
- HR:
-
Homologous recombination
- NHEJ:
-
Non-homologous end joining
- MMEJ:
-
Microhomology-mediated end joining
- HDAC:
-
Histone deacetylase
- HDAC:
-
Histone deacetylase inhibitor
- DSB:
-
Double-stranded DNA break
- PARP:
-
Poly (ADP-ribose) polymerase
- PARPi:
-
Poly (ADP-ribose) polymerase inhibitor
- PRC:
-
Polycomb repressive complex
- miRNA:
-
Micro-RNA
- siRNA:
-
Small interference-RNA
- LncRNA:
-
Long non-coding RNA
- RNAi:
-
RNA interference
- H3K4:
-
Histone H3 lysine 4
- H3K4me:
-
Methylated histone H3 lysine 4
- H3K27me:
-
Methylated histone H3 lysine 27
- H3K36me:
-
Methylated histone H3 lysine 36
- SAHA:
-
Suberoylanilide hydroxamic acid
- PARylation:
-
Poly ADP ribosylation
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Acknowledgements
I apologize to those authors whose work could not be cited due to space limitations. I thank Rebecca Jackson for editing a draft of this manuscript. This work was supported by a Singapore Ministry of Education Academic Research Fund (MOE2016-T2-2-063).
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Chen, E.S. Targeting epigenetics using synthetic lethality in precision medicine. Cell. Mol. Life Sci. 75, 3381–3392 (2018). https://doi.org/10.1007/s00018-018-2866-0
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DOI: https://doi.org/10.1007/s00018-018-2866-0