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approvals is rapidly increasing. The first two tyrosine kinases to be targeted by mAbs were the growth factor
receptors EGFR and HER2. However, these treatments are currently being challenged by recently emerging
therapeutics as a result of their associated side effects and the development of resistance.

KDMS AND TKI RESISTANCE
While the relationship between chemotherapy and epigenetics has been widely discussed [51,52] , emerging
evidence indicates that specific epigenetic effectors are also crucial for the development of resistance to
TKIs in the treatment of cancer.

Histones post-translational modifications (HPTMs) provide a mechanism for the regulation of gene expression
that is transmissible from parent to offspring. The globular domain and unstructured C- or N-terminal tails of
histones are subject to various covalent modifications including acetylation, phosphorylation and methylation
[53]
as well as the additions of large groups such as ubiquitin and ADP-ribose .
These HPTMs contribute to the control of gene expression in a context-dependent manner, by influencing
[53]
the compaction of chromatin or through signaling and recruitment of other protein complexes . An
appropriate balance between the stability and dynamics of HPTMs is required for accurate gene expression.
Carcinogenesis and tumorigenesis are highly dependent on the dysregulation of normal gene expression
[54]
and thus, HPTMs such as methylation and demethylation, play a critical role in tumour progression . As
a result, enzymes that catalyse the PTMs (e.g., histone lysine methylases) and their removal (e.g., histone
lysine demethylases) are actively being pursued as small-molecule targets for the development of new
oncology therapeutics.

KDMs are a group of enzymes that catalyze the removal of mono- (me1), di- (me2) and tri-methyl (me3)
[55]
marks on histones lysine residues . In particular, genes encoding for various KDMs have been found to be
overexpressed in several cancers [56-58] . In addition to this, some KDMs have been found to confer resistance
to established TKIs [Table 1].

Over 20 KDMs enzymes have been identified thus far.

KDMs can be classified into two broad categories, depending on their catalytic mechanism of action and
sequence homology: (1) lysine-specific demethylases (LSDs or KDM1 family); (2) Jumonji C-containing
[59]
histone demethylases (JmjC KDMs or KDM2-8 families) .
Both categories of KDMs use oxidative mechanisms to catalyze N-methyl-lysine demethylation albeit
in somewhat different manners. LSDs employ Flavin adenine dinucleotide and electron transfer in their
mechanism of action. As a result of this, LSDs are unable to demethylate tri-methylated lysine residues on
histones since the required electron lone pair is only present on mono- and di-methylated histones . The
[59]
second family of JmjC KDMs uses 2-oxoglutarate and O as co-substrate, with Fe(II) employed as a cofactor
2
[59]
for the enzymatic oxygenase reaction . This means that JmjC demethylases can remove mono-, di- and
[59]
tri-methyl marks on lysine residues of histones .
The exact biological functions of KDMs are poorly understood. Having said this, there is significant
evidence to suggest that many of these enzymes play an important role in the early stages of growth,
development and differentiation of embryonic stem cells [60,61] . This is evidenced by pre-clinical experiments
demonstrating that knockdown of KDM8 in mice embryos leads to protein 53 (p53) upregulation and
[63]
[62]
thus, resulting in active resorption at early stages of development . Strobl-Mazzulla et al. also report
that KDM4A is required for the expression of neural crest specifier genes in embryonic chicken since
knockdown of KDM4A in these cells leads to a significant decrease in the expression of the said genes.