Abstract B041: PROTAC-mediated degradation of TACC3 sensitizes tumors to taxanes and induces apoptosis in FGFR3–TACC3 fusion cancers
Although multiple solid and hematological cancers often respond to anti-mitotic drugs such as taxanes, vinca alkaloids, maytansinoid and dolastatin analogs and other compounds, the efficacy of the treatment is limited by dose-limiting toxicity and persistent residual cancer cells. To identify mediators of cancer cell persistence to anti-mitotic agents we performed a genome-wide CRISPR editing screen in cancer cells treated with taxanes. The most essential gene for survival under taxane treatment in our screen was Transforming Acidic Coiled-Coil containing protein 3 (TACC3). Follow-up validation experiments using CRISPR-mediated single-gene knock-out (KO) confirmed that ablation of TACC3 sensitized tumor cells to multiple anti-mitotic drug classes. Cancer cell lines with centrosome amplification were strongly sensitized, and TACC3-KO xenografts were significantly more sensitive to taxane treatment compared to control, confirming in vivo relevance. Given that existing TACC3 small molecule ligands did not phenocopy this taxane sensitization effect, we designed Proteolysis Targeting Chimeras (PROTACs) to deplete TACC3. We synthesized and evaluated more than 100 PROTAC molecules and identified degraders that sensitize cancer cells to anti-mitotic drugs. One PROTAC (“C4”) degraded TACC3 at low nanomolar concentrations, strongly synergized with taxanes and eliminated residual cancer cells in vitro, had acceptable in vitro liver microsome stability, excellent predicted pharmacokinetic properties and no in vivo toxicity. Importantly, C4 sensitized triple-negative breast cancer xenografts to sub-efficacious taxane doses. In parallel, in-frame FGFR3–TACC3 fusions generate oncogenic driver proteins that promote tumor cell growth and survival. PROTAC C4 was also effective in degrading the FGFR3–TACC3 oncofusion in fusion-driven cancer cells, leading to suppression of downstream oncogenic signaling and induction of apoptosis. C4 eradicated fusion-positive cancer cells more efficiently than the FGFR inhibitor erdafitinib, while sparing fusion-negative cells. In vivo, treatment with C4 induced complete tumor regression and durable responses in FGFR3–TACC3-driven xenograft models without observed toxicity. Our data suggest that TACC3 degradation represents a dual therapeutic strategy: sensitizing tumors to anti-mitotic drugs and directly targeting FGFR3–TACC3 oncofusion-driven cancers. C4 was selected for further in vivo evaluation to establish proof of concept for this PROTAC-based therapeutic approach. Slawomir Andrzejewski, Keita Nakane, Olusiji Akinrinmade, Leandro Encarnacao Garcia, Seiya Kitamura, Eugen Dhimolea. PROTAC-mediated degradation of TACC3 sensitizes tumors to taxanes and induces apoptosis in FGFR3–TACC3 fusion cancers [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 B041.