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Page 2 of 18 Lee et al. J Cancer Metastasis Treat 2021;7:27 https://dx.doi.org/10.20517/2394-4722.2021.58

Keywords: Transcriptional addiction, transcription, oncogene addiction, cancer stem cell, thyroid hormone
receptors, steroid receptor coactivators, BET inhibitor, anaplastic thyroid cancer

INTRODUCTION
A prominent hallmark of cancer is gene dysregulation, leading to initiation of tumor development, distant
[1]
metastasis, and therapeutic resistance . Unlike normal cells, cancer cells require high levels of active
transcription to develop various survival programs and maintain uncontrolled growth . The need for high
[2]
transcription to propel cancer proliferation is supported by observations of over-expressed components in
transcriptional machinery in diverse cancers [1,3-5] . In particular, the development of aggressive and
therapeutically recalcitrant tumors such as anaplastic thyroid cancer (ATC) is known to rely on
characteristic patterns of gene expression (known as transcriptional addiction), despite a high level of
[6,7]
genetic heterogeneity . This transcriptional dependency requires perpetually active transcription, relying
on input from transcriptional key players including chromatin regulators. Such a higher activity exhibited
by transcription regulators has presented an opportunity for therapeutic intervention [6-10] .

[11]
ATC is a rare malignancy, but it is one of the most aggressive human solid cancers , accounting for 1%-2%
of all thyroid cancers, which are the most common endocrine malignancy [12,13] . ATC is extremely fast-
growing and invasive, and thus most cases present as stage IV disease with distant metastasis, making most
patients ineligible for surgery [14,15] . ATC is highly resistant to conventional therapy, and the median survival
of ATC patients is less than 6 months after diagnosis [11,16] . Currently there are no established therapeutic
options to improve overall survival of these patients [17,18] . American Thyroid Association guidelines and the
National Comprehensive Cancer Network Clinical Practice Guidelines for ATC recommend combination
therapy including surgery, chemotherapy, and/or radiotherapy to maximize clinical benefits [16,19] . Several
new tyrosine kinase inhibitors (TKIs) are currently under evaluation in phase II clinical trials for ATC. So
far only a combination therapy of dabrafenib with trametinib has been approved by the United States Food
and Drug Administration for BRAF-mutated ATC, which was based on the limited results from a phase II
clinical trial without definite evidence of benefits on survival . Therefore, development of new effective
[20]
therapeutic modalities is urgently needed.

One explanation to account for the difficulties in developing effective therapeutics for ATC is the lack of
well-defined driver mutations as well as clearly elucidated molecular mechanisms underlying the
carcinogenesis. ATC exhibits more genetic alterations and more extensive heterogeneity than other types of
thyroid cancers [21-23] . The high degree of intra- or inter-tumor heterogeneity [24,25] presents a huge challenge in
identifying effective therapeutic targets for ATC. Nevertheless, despite this genetic complexity, in a subset of
ATC, a characteristic transcriptional program frequently associated with super-enhancers emerges, resulting
in constitutive activation of some oncogenes [6,8-10,26] . Moreover, the expression of the oncogenes that are
driven by the super-enhancers has been shown to be particularly vulnerable to the effect of transcriptional
inhibitors as found in other cancers [27-31] . Thus, the molecular modulators of these transcriptional programs,
especially proteins that are important for the transcriptional control, have emerged as attractive targets for
aggressive cancers such as ATC. In this review, we will briefly review the transcriptional machinery process
and what is known about dysregulation of transcription in cancer development. We will then discuss how
the inhibitors which could disrupt transcription could impede cancer cell survival and proliferation. We will
also examine the challenges to be overcome before these inhibitors could be used for therapeutics for
patients.