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Updated: Feb 6, 2026
Mapping the Structure-Function Relationships of Disordered Oncogenic Transcription Factors Using Transcriptomic Analysis
Published on: June 27, 2020
Transcriptional targeting of oncogene addiction in medullary thyroid cancer
Anisley Valenciaga1, Motoyasu Saji1, Lianbo Yu2
1Division of Endocrinology, Diabetes, and Metabolism, The Ohio State University Wexner Medical Center and Arthur G. James Comprehensive Cancer Center, Columbus, Ohio, USA.
Abstract:
Metastatic medullary thyroid cancer (MTC) is incurable and FDA-approved kinase inhibitors that include oncogenic RET as a target do not result in complete responses. Association studies of human MTCs and murine models suggest that the CDK/RB pathway may be an alternative target. The objective of this study was to determine if CDKs represent therapeutic targets for MTC and to define mechanisms of activity. Using human MTC cells that are either sensitive or resistant to vandetanib, we demonstrate that palbociclib (CDK4/6 inhibitor) is not cytotoxic to MTC cells but that they are highly sensitive to dinaciclib (CDK1/2/5/9 inhibitor) accompanied by reduced CDK9 and RET protein and mRNA levels. CDK9 protein was highly expressed in 83 of 83 human MTCs and array-comparative genomic hybridization had copy number gain in 11 of 30 tumors. RNA sequencing demonstrated that RNA polymerase II-dependent transcription was markedly reduced by dinaciclib. The CDK7 inhibitor THZ1 also demonstrated high potency and reduced RET and CDK9 levels. ChIP-sequencing using H3K27Ac antibody identified a superenhancer in intron 1 of RET. Finally, combined inhibition of dinaciclib with a RET kinase inhibitor was synergistic. In summary, we have identified what we believe is a novel mechanism of RET transcription regulation that potentially can be exploited to improve RET therapeutic targeting.
Insights
Targeting cyclin-dependent kinases (CDKs) offers a new therapeutic strategy for metastatic medullary thyroid cancer (MTC). Dinaciclib, a CDK inhibitor, shows high sensitivity in MTC cells by reducing CDK9 and RET levels.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Metastatic medullary thyroid cancer (MTC) is currently incurable, with limited efficacy of existing FDA-approved RET kinase inhibitors.
- The CDK/RB pathway is suggested as a potential alternative therapeutic target for MTC based on preclinical studies.
Purpose of the Study:
- To investigate cyclin-dependent kinases (CDKs) as therapeutic targets in MTC.
- To elucidate the mechanisms of action for CDK inhibition in MTC treatment.
Main Methods:
- Utilized human MTC cell lines sensitive and resistant to vandetanib.
- Administered CDK inhibitors (palbociclib, dinaciclib, THZ1) and analyzed cytotoxicity, protein/mRNA levels, and transcriptional activity.
- Performed array-comparative genomic hybridization and ChIP-sequencing to identify genetic alterations and regulatory elements.
Main Results:
- Dinaciclib (CDK1/2/5/9 inhibitor) demonstrated high sensitivity in MTC cells, reducing CDK9 and RET expression.
- CDK9 protein was highly expressed in all tested MTC samples, with copy number gains in a subset.
- Dinaciclib and THZ1 (CDK7 inhibitor) reduced RNA polymerase II-dependent transcription and RET/CDK9 levels, respectively.
- A RET superenhancer was identified, and combined dinaciclib and RET inhibitor therapy showed synergistic effects.
Conclusions:
- CDK inhibition, particularly targeting CDK9, represents a promising therapeutic strategy for MTC.
- A novel mechanism of RET transcription regulation involving a superenhancer has been identified.
- Combined CDK and RET inhibition may overcome resistance and improve treatment outcomes for MTC.
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