Abstract 1644: Novel CDK9 degrader XY0597 potently inhibits gastroesophageal cancer growth and overcome resistance by increasing chromatin accessibility and down-regulating YAP/TEAD signaling

Gastroesophageal cancer (GEAC) consists of upper GI malignancies of the esophagus, gastroesophageal junction, or stomach. Despite recent advancements in treatment modalities, GEAC remains a major health burden and listed as the second leading cause of cancer-related deaths globally. GEAC poses a significant challenge with short survival and lack of effective therapeutics. Thus, uncovering novel targets is urgent need. Cyclin-dependent kinase 9 (CDK9), one of the transcription-associated CDKs, has been implicated in regulation of transcription via RNA Pol II pausing/release, and epigenetic modification of genes that contribute to tumorigenesis. However, the functional role of CDK9 and its potential targeting in GEAC remain largely unknown. In this study, we demonstrated that nuclear CDK9 expression was significantly elevated in primary GEAC tumor tissues including PDXs compared to normal tissues, in association with poor survival. Moreover, we developed a novel CDK9 degrader, YX0597 and showed that YX0597 strongly suppresses CDK9 expression, inhibits RNA Pol II Serine 2 phosphorylation and dramatically decrease its target MCL-1 that accompanied by potently inhibition of GEAC cell growth, decreased tumor cell invasion and tumor sphere formation especially in radiation resistant tumor cells. Mechanistically, YX0597 strongly enhanced chromatin accessibility and activated epigenetically silenced genes. Further, both CDK9 and YAP1 colocalized in tumor tissues and significantly correlated in GEAC; and RNAseq revealed YAP1, TEAD4 and its targets (CTGF, Cyr61) were dramatically reduced upon XY0597 treatment that correspond to CDK9 inhibition. Correspondingly, XY0597 strongly suppress expression of CDK9, MCL-1, YAP1, YAP1 transcription factor TEAD4 in radiation resistant cells compared to parental cells and showed more potently suppressed radiation resistant tumor cell growth in vitro and in vivo. Most importantly, the combination of CDK9 degrader XY0597 and a novel YAP1/TEAD inhibitor, VT00278, synergistically attenuated resistant tumor growth and progression in vitro and in the PDX model. Taken together, our studies open a new avenue for targeting CDK9 hyperactivated GEAC tumors especially in combination with YAP1/TEAD inhibition. Citation Format: Yan-ting Yann Zhang, Mikel Ghelfi, Yu Xue, Haiying Chen, Gennaro Calendo, Dipti Athavale, Curt Balch, Xiaodan Yao, Woonbok Chung, Luke Chen, Francis Spitz, Generosa Grana, Jia Zhou, Jean-Pierre Issa, Shumei Song. Novel CDK9 degrader XY0597 potently inhibits gastroesophageal cancer growth and overcome resistance by increasing chromatin accessibility and down-regulating YAP/TEAD signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1644.