CDK9 Degradation Suppresses Gastroesophageal Cancer Growth and Overcomes Radiation Resistance through Chromatin Remodeling and YAP1/TEAD Downregulation.

Authors

Yan-Ting Yann Zhang, Mikel Ghelfi, Yu Xue, Haiying Chen, Gennaro Calendo, Generosa Grana, Yuan Li, Dipti Athavale, Curt Balch, Xiaodan Yao, Woonbok Chung, Zhenning Wang, Vladimir Khazak, Francis Spitz, Jean-Pierre Issa, Jia Zhou, Shumei Song

Published in

Cancer letters. Pages 218916. Oct 20, 2026. Epub Oct 20, 2026.

Abstract

Gastroesophageal adenocarcinoma (GEAC) remains a highly aggressive malignancy with limited effective targeted therapies. Cyclin-dependent kinase 9 (CDK9), a key regulator of transcriptional elongation, has been implicated in oncogenic processes across multiple cancer types; however, its functional role and therapeutic potential in GEAC remain poorly defined. In this study, we systematically investigated CDK9 expression, function, and therapeutic targeting in GEAC, with particular emphasis on its interaction with the YAP/TEAD signaling axis. Immunohistochemical analysis of primary GEAC tumors and patient-derived xenografts revealed elevated CDK9 expression, which correlated with poor patient survival. Mechanistic studies using immunofluorescence and co-immunoprecipitation demonstrated a reciprocal regulatory interaction between CDK9 and YAP1, promoting transcriptional programs associated with tumor progression and radiation resistance. We developed novel CDK9-targeting proteolysis-targeting chimeras (PROTACs) and identified YX0597 as a potent CDK9 degrader. YX0597 effectively suppressed RNAP II Ser2 phosphorylation (RNAP II P-S2) and downregulated oncogenic drivers, including MCL-1. Functionally, CDK9 degradation markedly inhibited GEAC cell proliferation, invasion, and tumor sphere formation, with enhanced efficacy in radiation-resistant cells. Integrated RNA sequencing and ATAC sequencing revealed that CDK9 degradation increased chromatin accessibility, reactivated epigenetically silenced genes, and profoundly suppressed YAP/TEAD transcriptional activity. These coordinated transcriptional and epigenetic alterations disrupted oncogenic homeostasis, resulting in broad cytotoxicity. Importantly, co-targeting CDK9 and YAP/TEAD signaling produced strong synergistic antitumor effects in vitro and in vivo. Collectively, our findings identify CDK9 as a critical oncogenic driver in GEAC and highlight CDK9 degradation, particularly in combination with YAP/TEAD inhibition, as a promising therapeutic strategy for refractory GEAC.

PMID:
42901435
Bibliographic data and abstract were imported from PubMed on 21 Oct 2026.

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