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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 331

In line with these results, KDM1A, was found to promote liver cancer cells’ resistance also to the TKI
[72]
sorafenib . In their publication, the authors reported an increased expression of KDM1A in sorafenib-
resistance hepatocellular carcinoma cells. Furthermore, the inhibition of KDM1A using two potent
[79]
KDM1A inhibitors, GSK2879552 and pargyline [80,81] was found to re-sensitize the same cells to the effect
of sorafenib, partly through suppression of the Wnt/b-catenin signalling pathway and through reduction
[72]
of the population of cancer stem cell-like cells . Signalling mediated by the Wnt family of glycoproteins is
one of the most important mechanisms that direct cell proliferation, polarity and determine cell fate during
embryonic development and tissue homeostasis . As a result of this, alterations in the Wnt pathway are
[82]
often linked to cancer, amongst other diseases.

Other KDMs have also been implicated in the development of TKIs resistance, although their roles in
this context need to be furtherly investigated. KDM5C was found to be a critical epigenetic modulator
in the development of resistance to sunitinib in two different cancer cell lines of Lewis lung carcinoma
[75]
[76]
and RCC . Zimmermannova et al. have also reported the aberration of the KDM6A gene in imatinib-
resistant cell lines of TEL-ABL-positive acute lymphoblastic leukaemia. In contrast with this finding, the
[76]
aberration of this gene did not result in the expression of aberrant KDM6A protein , so further research
is required to fully determine the involvement of this demethylase in the development of TKI resistance in
this cancer type.

Taken together this experimental evidence indicates that KDMs play key roles in the development of
resistance to TKIs in several cancer types. Recent evidence also provides a suitable rationale to consider
the use of new therapies that can be used to combat this phenomenon and prevent further development
of cancer drug resistance. One approach could be to consider the use of specific KDM inhibitors to re-
sensitize cells to tyrosine kinase target therapies. The data presented in this article also suggest that
combination therapies that make use of TKIs and KDM inhibitors could possibly prevent, or reverse, the
acquisition of resistance through epigenetic modulations and thus, could offer an attractive therapeutic
strategy for certain cancers. In this context, it will be important to employ genetic and epigenetic
stratification techniques to select patients that are more likely to benefit from the combination between
TKIs and KDM inhibitors.

CONCLUSION
To conclude, targeting KDMs is currently an active area of research in the development of new epigenetic
drugs. Taking into account that many KDMs have been found to be amplified or overexpressed in a
wide variety of human cancers and have been shown to play critical roles in mediating TKI resistance,
these enzymes could be considered to be very attractive targets for the development of new therapeutic
combinations.

DECLARATIONS
Authors’ contributions
Made substantial contributions to conception and design: White JC, Pucci P, Crea F
Made substantial contribution in drafting the article and acquisition of the main literature: White JC
Contributed to the writing of the manuscript and critical revising: Pucci P, Crea F
Made substantial contribution in the revision process: White JC, Pucci P
Gave final approval of the submitted version and revised version to be submitted: Crea F

Availability of data and materials
Not applicable.