Targeting Histone Epigenetic Modifications and DNA Damage Responses in Synthetic Lethality Strategies in Cancer?

Abstract

Synthetic lethality strategies are likely to be integrated in effective and specific cancer treatments. These strategies combine different specific targets, either in similar or cooperating pathways. Chromatin remodeling underlies, directly or indirectly, all processes of tumor biology. In this context, the combined targeting of proteins associated with different aspects of chromatin remodeling can be exploited to find new alternative targets or to improve treatment for specific individual tumors or patients. There are two major types of proteins, epigenetic modifiers of histones and nuclear or chromatin kinases, all of which are druggable targets. Among epigenetic enzymes, there are four major families: histones acetylases, deacetylases, methylases and demethylases. All these enzymes are druggable. Among chromatin kinases are those associated with DNA damage responses, such as Aurora A/B, Haspin, ATM, ATR, DNA-PK and VRK1—a nucleosomal histone kinase. All these proteins converge on the dynamic regulation chromatin organization, and its functions condition the tumor cell viability. Therefore, the combined targeting of these epigenetic enzymes, in synthetic lethality strategies, can sensitize tumor cells to toxic DNA-damage-based treatments, reducing their toxicity and the selective pressure for tumor resistance and increasing their immunogenicity, which will lead to an improvement in disease-free survival and quality of life.

Combination Treatment Strategies to Overcome PARP Inhibitor Resistance

“…DDR genes are epigenetically modified to cause transcriptional silencing and the loss of DNA repair capacity in cancers. These epigenetic modifications have been reported to affect PARPis' sensitivity [115,116]. Therefore, epigenetic inhibitors including the DNA methyltransferase inhibitor (DMNTi) and histone deacetylation inhibitor (HDACi) have been considered to enhance PARPi treatment outcomes by modifying epigenetic marks associated with resistance.…”

SETDB1 as a cancer target: challenges and perspectives in drug design

“…In other words, an individual's gene behavior is not solely determined by their genetic makeup; it can also be influenced by changes to the way their genes are expressed through the epigenetic machinery. 13–17 Additionally, it provides a framework for comprehending individual distinctions and the uniqueness of certain cells, tissues, or organs. 18,19 Small-interfering RNAs, DNA methylation, histone modifications and nucleosome positioning are the main categories of interconnected mechanisms that can affect the gene stability, DNA folding, chromatin compaction, and ultimately nuclear organization and gene expression.…”

The role of VRK1 in chromatin remodeling: regulation of histone post-translational modifications and epigenetic enzymes

“…HDAC classes I, II and IV NSCLC 90 Multiple myeloma 91 Ovarian cancer 92,93 Glioblastoma NSCLC 110 Acute myeloid leukemia 111 Merkel cell carcinoma 112 Breast cancer 113 In this context, treating tumor cells with these inhibitors can disrupt different biological processes including gene transcription, replication and DDR. Most of them show enzymatic inhibition occupying the site of the substrate in their binding pockets 114 . For example, tazemetostat inhibits wild-type and mutant EZH2 activity and has mainly been used in different lymphoma and sarcoma studies 102,103 .…”

“…This combination has shown potential to resensitize refractory-multiple myeloma cells 116,117 In conclusion, the manipulation of chromatin by epidrugs, in combination with other conventional treatments such as chemotherapy, radiation, immunotherapy or other inhibitors, can play a major role by increasing the tumor cell sensitivity. This potentially successful approach is known as synthetic lethality, which is based on the combination of two treatments targeting different pathways that promote tumor cell death 114 .…”

“…In the meantime, combinatorial approaches have been increasingly investigated in clinical trials in order to further enhance the efficacy of cancer therapy 25,114 . In this work, we demonstrated that specific pharmacological inhibition of VRK1 showed similar effects to VRK1 depletion in cells.…”