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Page 114 Aziz et al. Cancer Drug Resist 2020;3:113-6 I http://dx.doi.org/10.20517/cdr.2020.06

The tyrosine kinase inhibitors (TKIs) have an important role in cancer therapy. They are effective against
many cancers, both solid and liquid. They have particularly been used to inhibit the oncogenic activity
associated with epidermal growth factor receptor (EGFR), a receptor tyrosine kinase. However, acquired
[5,6]
[7]
[4]
resistance against EGFR-TKIs is well-studied with reports on its epigenetic regulation . White et al.
reviewed the subject by evaluating a role of histone lysine demethylases in resistance against TKIs. Up-
regulation of these demethylases leads to resistance against TKIs. For example, amplification of KDM5A
gene in breast cancer correlates with erlotinib resistance, as well as with gefitinib resistance in lung
cancer. Erlotinib and gefitinib are first generation EGFR-TKIs. Similarly, KDM1A, also known as lysine-
specific histone demethylase 1A, mediates resistance against sorafenib in liver cancer cells. Sorafenib is
a kinase inhibitor effective against rapidly accelerated fibrosarcoma, vascular endothelial growth factor
receptor, and platelet-derived growth factor receptor kinases. Based on this evidence, inhibition of lysine
demethylases can be an effective strategy to overcome resistance against TKIs.

[8]
Ovarian cancer is the most lethal gynecological cancer, with a reported epigenetic basis of drug resistance .
Platinum-based anticancer drugs are commonly used to treat ovarian cancer but the tumors often progress
within the first two years of treatment. Schwarzenbach and Gahan discussed the epigenetic signatures,
[9]
such as DNA methylation, histone modifications, and miRNA deregulation, in cis- or carboplatin resistant
ovarian cancers. Such knowledge can help identify patients who will respond favorably to platinum-
based therapies vs. those who will not. This is a step towards personalized medicine in cancer, a concept
that is increasingly attracting the attention of cancer researchers [10-12] . Breast cancer is another cancer
that is frequently diagnosed in females and which remains a leading cause of cancer-related deaths in
females worldwide. Among the many mechanisms, epithelial-to-mesenchymal transition (EMT) and the
acquisition of cancer stem-like phenotype provide plasticity to breast cancer cells, rendering these cells
[13]
highly invasive, metastatic, and resistant to therapies. The article by Ponnusamy et al. provides a better
understanding of epigenetic modifications underpinning the cellular reprogramming, particularly the
EMT and stem cell phenotype. Such knowledge is essential to design future therapies to overcome cancer
[14]
drug resistance. On a similar topic, the research article by Seno et al. describes the cytotoxic action of
daunorubicin, a topoisomerase II inhibitor, against mouse induced pluripotent stem cells-derived cancer
stem cells.

The relevance of epigenetic events is not limited to solid tumors. In acute lymphoblastic leukemia, a
common childhood malignancy, there is an increasing realization that genetic changes are not enough
to describe the observed chemoresistance and the resulting relapse. As a result, researchers have started
looking at the epigenetic changes as a possible answer to this problem and this is the topic of discussion
[15]
[16]
in the article by Meyer et al. . Further, a cell organelle that is relatively less studied in the context of
epigenetic regulation of drug resistance is the centrosome. The centrosome plays a very important role
during cell division, ensuring proper distribution of cellular components among daughter cells. Any
aberrant functioning of centrosomes, through epigenetic events, can compromise the integrity of cells,
[17]
resulting in genetic instability. The article by Jia et al. touches upon this important topic of understanding
epigenetic changes in the centrosome as relevant to cancer drug resistance.

The focus on immune cells-cancer cells interactions and the reprograming of cancer cells enabling evasion
of host immune system over the past several years has brought cancer immunology to the forefront of
cancer research . In particular, immune checkpoints block the ability of the immune system to act on
[18]
cancer cells. Thus, immune checkpoint inhibitors have been evaluated to boost up the immune system
and potentiate T-cells to recognize and attack tumor cells. As seen in almost all anti-cancer therapies,
[19]
resistance against immune checkpoint inhibitors has also been reported. Peixoto et al. described the
epigenetic modifications that underline the resistance against immunotherapy.