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White et al. Cancer Drug Resist 2019;2:326-34 Cancer
DOI: 10.20517/cdr.2019.16 Drug Resistance

Review Open Access

The role of histone lysine demethylases in cancer
cells’ resistance to tyrosine kinase inhibitors

Jasmine Cassar White, Perla Pucci, Francesco Crea

School of Life Health and Chemical Sciences, The Open University, Walton Hall, Milton Keynes MK76AA, UK.

Correspondence to: Dr. Perla Pucci and Dr. Francesco Crea, School of Life Health and Chemical Sciences, The Open University,
Walton Hall, Milton Keynes MK76AA, UK. E-mail: perla.pucci@open.ac.uk; francesco.crea@open.ac.uk

How to cite this article: White JC, Pucci P, Crea F. The role of histone lysine demethylases in cancer cells’ resistance to tyrosine
kinase inhibitors. Cancer Drug Resist 2019;2:326-34. http://dx.doi.org/10.20517/cdr.2019.16

Received: 22 Dec 2018 First Decision: 12 Feb 2019 Revised: 22 Feb 2019 Accepted: 4 Mar 2019 Published: 19 Jun 2019

Science Editor: Aamir Ahmad Copy Editor: Cai-Hong Wang Production Editor: Huan-Liang Wu

Abstract
Current cancer therapies are often associated with treatment failure and reduced patients’ survival due to drug
resistance. There are various mechanisms involved in the acquisition of cancer drug resistance, including the selection
of advantageous mutations, overexpression of transporter proteins and epigenetic alterations. In this context, epigenetic
alterations refer to chromatin-mediated regulation of gene expression that results in heritable changes in the cellular
phenotype. There is an ever-growing body of evidence suggesting that epigenetic mechanisms play an important role in
bringing about drug resistance in cancer cells. While the relationship between chemotherapy and epigenetics has been
widely discussed, emerging evidence indicates that specific epigenetic effectors are also crucial for the development of
resistance to tyrosine kinase inhibitors (TKIs). One particular gene that encodes the histone lysine demethylase KDM5A
is overexpressed in several cancers. In breast cancer tissues, cells with KDM5A gene amplification were found to be
more resistant to erlotinib, an inhibitor of the tyrosine kinase epidermal growth factor receptor (EGFR), when compared
to cells without the same amplification. KDM5A was also shown to mediate resistance to a second EGFR inhibitor called
gefitinib, in EGFR-mutant lung cancer cell lines. This evidence indicates that KDM5A could activate alternative survival
pathways involved in overcoming EGFR inhibition. In line with these results, another histone demethylase (i.e., KDM1A)
promotes liver cancer cells’ resistance to the TKI sorafenib. Current evidence provides a suitable rationale to consider the
use of specific KDMs inhibitors to sensitize cells to tyrosine kinase targeted therapies and thus, presents an opportunity
to prevent the further development of drug resistance. This review discusses the involvement of histone lysine
demethylases in the development of resistance to TKI and highlights the importance to develop new cancer treatment
regimens to counteract this phenomenon.

Keywords: Epigenetics, drug resistance, cancer

© The Author(s) 2019. Open Access This article is licensed under a Creative Commons Attribution 4.0
International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long
as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license,
and indicate if changes were made.

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