Pharmacologic inhibition of SOX9-CDK4 by CYD-4-61 impairs gastric adenocarcinoma growth and amplifies anti-PD-1 response
Year: 2026
Type: article
Abstract: Gastric adenocarcinoma (GAC) remains a leading cause of cancer-related mortality, particularly in patients with peritoneal carcinomatosis, for whom effective therapies are limited. We investigated the therapeutic efficacy and molecular mechanism of CYD-4-61, a BAX activator, using human GAC cell lines, patient-derived xenograft models, genetically engineered mouse models, and a syngeneic mouse model. CYD-4-61 potently inhibited tumor cell proliferation, induced apoptosis, and suppressed cancer stem cell-like properties, with enhanced activity in radiation-resistant GAC cells. Mechanistically, CYD-4-61 activated the BAX-caspase pathway, leading to SOX9 protein reduction. Integrated bulk and single-cell transcriptomic analyses identified SOX9-dependent transcriptional programs as major targets of CYD-4-61. Functional rescue experiments together with chromatin immunoprecipitation and CUT&RUN analyses supported CDK4 as a SOX9-regulated gene and demonstrated suppression of the SOX9-CDK4 regulatory axis following CYD-4-61 treatment. In multiple preclinical models, CYD-4-61 significantly inhibited tumor growth and improved the therapeutic response to anti-programmed cell death protein 1 (PD-1) therapy while modulating the tumor immune microenvironment. Clinically, co-expression of SOX9 and CDK4 was associated with diffuse-type GAC and poor patient outcomes. These findings identify the BAX-SOX9-CDK4 axis as an important mechanism contributing to the antitumor activity of CYD-4-61 and provide a strong preclinical rationale for its further development as a therapeutic strategy for aggressive GAC.
Source: Cancer Letters
Authors: Gengyi Zou, Katsuhiro Yoshimura, Yibo Fan, Liyong Zeng, Aryanasingh S. Bhati, Bansi R. Vanpariya, Enyu Dai, Kohei Yamashita, Lingzhi Wang, Jingjing Wu, Shan Shao, Ailing W. Scott, Jiankang Jin, Melissa Pool Pizzi, Xiaodan Yao, Calena-Abel Brown, Fang Cao, Ruiping Wang, Xueshuai Han, Jun Li, Haiying Chen, Pingyuan Wang, Linghua Wang, Bin Liu, Jia Zhou, Yuan-Hung Lo, Qiong Gan, Rebecca Waters, Feng Yin, Shumei Song, Jaffer A. Ajani, Shilpa S. Dhar
Institutions: The University of Texas MD Anderson Cancer Center, Louisiana State University Health Sciences Center Shreveport, Hamamatsu University, Hamamatsu University School of Medicine, University of Houston, The University of Texas Medical Branch at Galveston, Coriell Institute For Medical Research
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,960
Awards: G1299882215, G4360070759, G6678286902, Molecular Biomarkers as Classifiers to Individualize Therapy of Esophagus Cancer, Inhibition of Hedgehog Signaling in Gli-1+Adeno CA of the Esoph or GE junction, G8444441947, G9000233541, Mechanisms of CDH1-inactivated advanced gastric adenocarcinoma tumorigenesis, Common Stem Cell of Origin for Junctional and Gastric Adenocarcinoma
OpenAlex ID: W7201833255