Abstract B045: Targeted degradation of cyclin T1 constrains transcription elongation and triggers tumour cell apoptosis

Abstract

Transcriptional dysregulation is a hallmark of cancer and is frequently driven by oncogenic alterations that rewire downstream gene-expression programmes. Although kinase inhibitors targeting upstream oncogenic drivers can produce clinical benefit, responses are often limited by acquired resistance and pathway adaptation. Targeting transcriptional dependencies therefore represents an alternative therapeutic strategy. The positive transcription elongation factor b complex, composed of CDK9 and Cyclin T1(CCNT1), is a central regulator of RNA polymerase II transcriptional elongation and supports the expression of genes required for tumour cell survival. However, conventional CDK9 inhibitors often lack sufficient selectivity and are associated with dose-limiting toxicities. Here, we report the rational design of a novel CCNT1-targeting binder and its application in biological proteolysis-targeting chimeras designed to selectively degrade Cyclin T1. The degrader platform combines E3 ubiquitin ligase recruitment with a dual-peptide CCNT1-binding module derived from the pTEFb-interacting partners AFF4 and HIV-TAT. This engineered recruitment strategy enabled robust and selective depletion of both tagged and endogenous CCNT1 in cancer cells. CCNT1 degradation was accompanied by destabilisation of its catalytic partner CDK9 and reduced phosphorylation of RNA polymerase II, consistent with suppression of transcriptional elongation. Functionally, CCNT1-targeted degradation produced marked anti-tumour effects in lung cancer models. Degrader-treated cells showed impaired proliferative capacity, reduced colony formation, cell-cycle disruption across multiple checkpoints, and induction of apoptosis. These findings demonstrate that selective degradation of CCNT1 can effectively collapse pTEFb-dependent transcriptional programmes and compromise tumour cell fitness. Together, our study establishes a novel CCNT1 binder-enabled degrader strategy as a translational approach to targeting transcriptional addiction in cancer. By moving beyond catalytic CDK9 inhibition and directly eliminating the Cyclin T1 scaffold, CCNT1-targeted degradation may offer a more selective and durable route for therapeutic intervention in transcriptionally dependent tumours. Janice Wenzheng Neng, Laura Blenkarn, Laura S. Itzhaki, Catherine H. Wilson. Targeted degradation of cyclin T1 constrains transcription elongation and triggers tumour cell apoptosis [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr B045.