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White et al. Cancer Drug Resist 2019;2:326-34 I http://dx.doi.org/10.20517/cdr.2019.16 Page 327

INTRODUCTION
The introduction of targeted therapies against cancer-specific molecules and signaling pathways led to
significant improvements in the quality of medical care for cancer, wider therapeutic indices and more
[1]
limited non-specific toxicities, when compared to earlier forms of cancer therapies . Tyrosine kinases
(TKs) are particularly important targets because they play a key role in the modulation of growth factor
[2]
signaling, therefore influencing many downstream pathways . In recent years, numerous tyrosine
[3,4]
kinase inhibitors (TKIs) have been developed as highly effective anti-tumor and anti-leukemic agents .
[5-7]
Unfortunately, intrinsic TKI resistance and acquired therapeutic resistance [8-10] to TKIs often develops
along the course of therapy, reducing TKIs clinical efficacy and hampering effective treatment of cancer.
There are many molecular mechanisms that are involved in the acquisition of resistance to TKIs, such as
mutation of drug targets, changes in drug metabolism and the over-expression of cancer drug resistance
[11]
transporter proteins that result in increased rates of drug efflux . Apart from this, tumors are highly
adaptable to the biological microenvironment and changes in the activation and inactivation patterns of
survival signaling pathways can also result in the emergence of drug resistance [12,13] . Epigenetic mechanisms
have been found to play an important role in generating drug resistance in cancer cells [14,15] . In this context,
epigenetic alterations refer to chromatin-mediated regulation of gene expression that results in heritable
[16]
changes in the cellular phenotype .
In this review we will focus on the role of a specific family of epigenetic effectors (i.e., histone lysine
demethylases, KDMs) in the context of TKIs resistance.

TYROSINE KINASES AND INHIBITORS: HYSIOLOGICAL FUNCTIONS AND RELEVANCE IN
CANCER
TKs are enzymes capable of selectively phosphorylating tyrosine residues in different substrates, resulting
in the activation of numerous proteins involved in the signal transduction cascade . Therefore TKs
[17]
play key roles in mediating biological processes such as cellular differentiation, metabolism, growth and
[18]
apoptosis in response to both external and internal stimuli . For example, FMS Like Tyrosine Kinase
3 (FLT3) is a class III TK cytokine receptor that is expressed on the surface of immature hematopoietic
progenitor cells and plays important roles in promoting the survival and correct growth of progenitor cells
[19]
and hence, the control of hematopoiesis . FLT3 mutations can be found in patients suffering from acute
myeloid leukaemias (AMLs) and B-cell acute lymphoblastic leukaemias (ALLs) and cause uncontrolled
receptor activation, constitutive FLT3 signalling and as a result, activation of the STAT4, RAS/MAPK and
[20]
PI3K pathways important for cell division, apoptosis and cell formation .

Due to their wide roles in many signaling pathways, the level of intra-cellular tyrosine kinase phosphorylation
must be tightly controlled; this is achieved through maintenance of the balance between TKs and their
antagonists, tyrosine phosphatases.

Despite being strictly regulated in physiological conditions, TKs may acquire aberrant functions caused
by various mechanisms including mutations and overexpression of the TK genes, leading to constitutive
[21]
oncogenic TKs activation and development of malignant phenotypes . There are four main mechanisms
resulting in the constitutive activation of receptor TKs in human cancers: (1) gain-of-function mutations;
(2) overexpression and genomic amplifications; (3) chromosomal rearrangements; and/or (4) autocrine
[17]
activation .
Gain-of-function mutations in TKs lead to abnormal downstream signal transduction and can be
exemplified by “driver mutations” that result in a selective growth advantage to cells. This is an important