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FR-03

A molecular glue–empowered strategy for enhancing sonodynamic therapy

via cyclin K degradation–induced DNA repair suppression

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Kai-Yun Cheng, Lo-Chueh Chu, Wei Chen*

1 Genomics Research Center, Academia Sinica, Taipei, Taiwan
* E-mail: wchen123@as.edu.tw (W.C.)

Abstract
The therapeutic efficacy of sonodynamic therapy (SDT) relies on the generation of reactive
oxygen species (ROS) to induce oxidative stress and DNA damage in tumor cells. However, its
effectiveness is often limited by the robust DNA repair mechanisms maintained in cancer cells.
Here, we present a synergistic approach combining SDT with a molecular glue, HQ461, which
selectively induces the degradation of Cyclin K (CCNK) and subsequently inhibits CDK12-
mediated transcription of DNA repair gene sets such as homologous recombination (HR) and
DNA damage response (DDR). This combination leads to synthetic lethality by amplifying
DNA damage while impairing the capacity of tumor cells to repair double-strand breaks. In
vitro, the combined treatment markedly enhanced γH2AX formation and apoptosis in HR-
proficient cancer cells. In vivo, ultrasound-triggered SDT paired with systemic HQ461
administration significantly suppressed tumor growth with minimal systemic toxicity. Our
study demonstrates that coupling molecular glue–mediated transcriptional reprogramming with
sonodynamic therapy represents a promising synthetic lethality strategy to sensitize solid
tumors to oxidative DNA damage and overcome intrinsic resistance mechanisms.

Keywords: Metal Organic Frameworks; Sonodynamic Therapy; Molecular glues; Targeted
protein degradation