Phenotypic screening converges on CDK9 inhibition as a therapeutic strategy in translocation renal cell carcinoma
Dharma R Thapa1, Riva Deodhar1, Adam Skepner2
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Abstract:
Translocation renal cell carcinoma (tRCC) is an aggressive kidney cancer driven by gene fusions of the TFE3 transcription factor. TFE3 is essential in tRCC but dispensable in normal cells, presenting an attractive but pharmacologically challenging therapeutic target. We show that the basic helix-loop-helix (bHLH) domain of TFE3 is crucial for chromatin binding and transcriptional function. Via a phenotypic screen of 25,000 compounds, we identified molecules that either displace or retain chromatin-bound TFE3. BRD6866, a compound trapping TFE3 on chromatin, emerged as a pan-CDK inhibitor. Mechanistically, its inhibition of CDK9 - a key regulator of transcriptional elongation - was linked to impaired TFE3 fusion activity. These effects were recapitulated by the CDK9-selective inhibitor enitociclib, which downregulated TFE3 targets and suppressed tRCC cell growth. Our findings nominate CDK9 inhibition as a therapeutic strategy in tRCC and demonstrate the utility of mechanism-informed phenotypic screening for challenging targets.
Insights
Researchers identified a new therapeutic strategy for translocation renal cell carcinoma (tRCC). Targeting CDK9, a key regulator, effectively suppressed tRCC cell growth by inhibiting the TFE3 fusion protein.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Translocation renal cell carcinoma (tRCC) is an aggressive kidney cancer.
- The TFE3 transcription factor is essential for tRCC but not normal cells, making it a challenging therapeutic target.
- The basic helix-loop-helix (bHLH) domain of TFE3 is critical for its function.
Purpose of the Study:
- To identify compounds that modulate chromatin-bound TFE3.
- To explore CDK9 inhibition as a therapeutic strategy for tRCC.
- To demonstrate the utility of mechanism-informed phenotypic screening.
Main Methods:
- Phenotypic screening of 25,000 compounds to identify modulators of chromatin-bound TFE3.
- Investigated the mechanism of action of identified compounds, including BRD6866.
- Utilized CDK9-selective inhibitors, such as enitociclib, to validate findings.
Main Results:
- Identified BRD6866, a compound that traps TFE3 on chromatin and acts as a pan-CDK inhibitor.
- Demonstrated that BRD6866 inhibits CDK9, impairing TFE3 fusion activity and downregulating TFE3 targets.
- Enitociclib, a CDK9 inhibitor, recapitulated these effects and suppressed tRCC cell growth.
Conclusions:
- CDK9 inhibition is a promising therapeutic strategy for translocation renal cell carcinoma.
- Mechanism-informed phenotypic screening is effective for targeting challenging therapeutic targets like TFE3.
- Targeting TFE3-driven tRCC through CDK9 inhibition offers a novel treatment avenue.
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