Combined CDK12/13 and BET inhibition as a therapeutic strategy in breast cancer

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dc.check.date2028-12-31
dc.contributor.advisorKrajewska, Malgorzata
dc.contributor.advisorO'Connor, Rosemary
dc.contributor.authorRehman, Faisalen
dc.date.accessioned2026-09-28T14:03:28Z
dc.date.available2026-09-28T14:03:28Z
dc.date.issued2026-03-31
dc.date.submitted2026-03-31
dc.description.abstractBackground: Breast cancer is the most common type of malignancy among women. Triple Negative Breast cancer (TNBC) is an aggressive subtype of breast cancer characterised by high genomic instability and limited targeted therapeutic options. Transcription Cyclin-dependent kinases, CDK12/13, are serine/threonine kinases that regulate the RNA Polymerase II elongation, mRNA processing and expression of DNA damage response genes. Dysregulation of CDK12/13 contributes to tumour progression and genomic instability. A study from our lab indicated potential for CDK12/13 inhibition as a therapeutic approach for TNBC. The aim of this thesis is to investigate the effect of dual inhibition of CDK12/13 with the JQ1 inhibitor of Bromodomain and extra-terminal domain (BET) family member BRD4 in TNBC model. Methods: Publicly available transcriptomic and proteomic clinical datasets were used to analyse the CDK12 and CDK13 expression patterns in breast cancer. Molecular modelling using AutoDock Vina was performed to investigate drug selectivity. Cell viability was evaluated using MTT and Crystal violet assays. Protein expression was analysed using western blotting. Apoptosis was analysed using Annexin V and Propidium iodide (PI) staining, while cell cycle distribution was analysed by propidium iodide (PI) staining using flow cytometry. Results: Analysis of transcriptomic and proteomic clinical data revealed that CDK12 and CDK13 are significantly overexpressed in breast cancer tissue compared to normal tissue. Molecular modelling studies demonstrated that SR4835 binds within the ATP-conserved binding pocket of CDK12/13. The sequence alignment analysis revealed 96.9% similarity between CDK12/13 in their protein kinase domain. Combination of SR4835 and JQ1 significantly reduced cell viability, induced DNA damage, promote caspase-dependent apoptosis, and arrested the cell cycle more than single agent treatment. Notably, SR4835 alone induced STAT3 phosphorylation and co-treatment with SR4835 and a neutralising IL6 antibody significantly suppressed STAT3 phosphorylation. Finally, SR4835 alone pronouncedly increased pSTAT3 phosphorylation, while JQ1 reduced it, and co-treatment reversed SR4835-induced STAT3 phosphorylation. Significance: Our study demonstrated that dual inhibition of CDK12/13 and BRD4 significantly reduced TNBC proliferation by inducing cell death and apoptosis, and blocked activation of the compensatory STAT3 pathway induced by CDK12/13 inhibition. This dual transcription-targeted strategy provides a promising therapeutic approach for TNBC and holds potential for further in vivo studies.en
dc.description.statusNot peer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationRehman, F. 2026. Combined CDK12/13 and BET inhibition as a therapeutic strategy in breast cancer. MRes Thesis, University College Cork.
dc.identifier.endpage182
dc.identifier.urihttps://hdl.handle.net/10468/19346
dc.language.isoenen
dc.publisherUniversity College Corken
dc.rights© 2026, Faisal Rehman.
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectCDK12/13en
dc.subjectBRD4en
dc.subjectTNBCen
dc.subjectTranscriptionen
dc.subjectRNA Polymerase IIen
dc.titleCombined CDK12/13 and BET inhibition as a therapeutic strategy in breast canceren
dc.typeMasters thesis (Research)en
dc.type.qualificationlevelMastersen
dc.type.qualificationnameMRes - Master of Researchen
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