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Page 12 of 18 Lee et al. J Cancer Metastasis Treat 2021;7:27 https://dx.doi.org/10.20517/2394-4722.2021.58

The efficacy of targeting the transcription-associated CDKs has also been shown in aggressive medullary
thyroid cancer (MTC) and ATC. The development and progression of MTC are known to be driven by the
gain of function mutations of the RET proto-oncogene. A super-enhancer in the intron 1 of the RET gene
[153]
provides the sensitivity to be targeted by CDK9 inhibitors alone or with a RET kinase inhibitor . ATC
cells that exhibit super-enhancers-mediated transcription addiction were shown to be sensitive to
[26]
[154]
transcription inhibition by the CDK7 or CDK12 inhibitor . However, intriguingly, MYC was not found
in the list of the super-enhancer-mediated or THZ1 (CDK7 inhibitor)-sensitive cancer genes in these
studies. Of note, previous findings reported that ATC cells heavily rely on MYC-driven transcriptional
addiction [110,125,155] and that the CDK7 inhibitor led to massive suppression of MYC-driven global
transcriptional amplification [8,10,156] . One possible explanation for these differences among studies could be
the use of different experimental models. Therefore, it would be important to develop additional
experimental models that could be comprehensively analyzed and validated. Furthermore, in view of the
importance of CSCs in chemoresistance and recurrence of ATC, the potential effects of inhibitors targeting
the transcription-associated CDKs on CSC activity should be evaluated and its underlying molecular
mechanisms elucidated. The fruitful outcome of such studies will broaden the availability of urgently
needed therapeutic targets for ATC.

CONCLUSION AND FUTURE PERSPECTIVES
ATC’s complex and heterogeneous genetic profiles with high transcriptional output enable continuous
development of survival programs in the face of current targeted therapies. Early studies showed multiple
upstream driver mutations to initiate carcinogenesis. More recent studies indicated that such driver
mutations initiated upstream could converge to trigger transcriptional responses as evidenced by global
genomic analyses. Mutations in transcriptional regulators such as components of SWI/SNF chromatin
remodeling complex, histone methyltransferases, and EIF1AX (a key component of the translational
preinitiation complex) were identified in ATC [22,23,146] , supporting the potential of transcriptional regulators
as therapeutic targets for ATC treatment.

Indeed, as presented in this review, our studies have provided the rationale for potential clinical trials using
small-molecule inhibitors such as JQ1 (BET inhibitor), PLX51107 (BET inhibitor), and SI-2 (SRC-3
inhibitor) to target the transcriptional regulators in ATC patients. Targeting other key components of the
transcriptional machinery, such as chromatin regulators, the mediator, and other transcriptional
coactivators, would also have profound effects on the final manifestation of oncogenic transcriptional
responses. Thus, the identification of small-molecule inhibitors targeting them (or activators for TRs) is a
promising strategy for effective ATC treatment.

Several important questions require further investigations to bridge the gap between preclinical studies and
clinical application. Therapeutic windows for each inhibitor would have to be assessed in clinical trials
because the transcriptional inhibition can affect normal as well as cancer cells. Defining the therapeutic
windows for selectively targeting the cancer transcription program could avoid side effects thereby
enhancing the well-being of the patients. Further, identification of transcription inhibitors which could
deplete CSCs in ATC could minimize chemoresistance and recurrence. The elucidation of how the key
players regulating the transcription programs lead to depleting of CSCs would certainly expand the choice
of therapeutic targets for ATC to further benefit patients.

DECLARATIONS
Acknowledgments
We wish to thank all our colleagues and collaborators who have contributed to the work presented in this