Academic Journal
Pharmacologic inhibition of SOX9-CDK4 by CYD-4-61 impairs gastric adenocarcinoma growth and amplifies anti-PD-1 response.
| Τίτλος: | Pharmacologic inhibition of SOX9-CDK4 by CYD-4-61 impairs gastric adenocarcinoma growth and amplifies anti-PD-1 response. |
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| Συγγραφείς: | Zou G; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Pharmacology, Toxicology and Neuroscience, LSU Health Shreveport, Shreveport, LA, USA., Yoshimura K; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan., Fan Y; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Pharmacy Practice and Translational Research, College of Pharmacy, University of Houston, Houston, TX, USA., Zeng L; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Bhati AS; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Vanpariya BR; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Dai E; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Yamashita K; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Wang L; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Wu J; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Shao S; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Scott AW; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Jin J; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Pizzi MP; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Yao X; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Brown CA; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Cao F; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Wang R; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Han X; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Li J; Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA., Chen H; Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA., Wang P; Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA., Wang L; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Liu B; Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Zhou J; Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA., Lo YH; Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Gan Q; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Waters R; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Yin F; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Song S; Coriell Institute for Medical Research, NJ, USA., Ajani JA; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: jajani@mdanderson.org., Dhar SS; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: ssdhar@mdanderson.org. |
| Πηγή: | Cancer letters [Cancer Lett] 2026 Oct 28; Vol. 659, pp. 218777. Date of Electronic Publication: 2026 Aug 07. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Elsevier Science Ireland Country of Publication: Ireland NLM ID: 7600053 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1872-7980 (Electronic) Linking ISSN: 03043835 NLM ISO Abbreviation: Cancer Lett Subsets: MEDLINE |
| Imprint Name(s): | Publication: Limerick : Elsevier Science Ireland Original Publication: Amsterdam, Elsevier/North-Holland. |
| Ιατρικοί όροι (MeSH): | Stomach Neoplasms*/drug therapy , Stomach Neoplasms*/pathology , Stomach Neoplasms*/genetics , Stomach Neoplasms*/metabolism , SOX9 Transcription Factor*/antagonists & inhibitors , SOX9 Transcription Factor*/metabolism , SOX9 Transcription Factor*/genetics , Adenocarcinoma*/drug therapy , Adenocarcinoma*/pathology , Adenocarcinoma*/genetics , Adenocarcinoma*/metabolism , Cyclin-Dependent Kinase 4*/antagonists & inhibitors , Cyclin-Dependent Kinase 4*/metabolism , Cyclin-Dependent Kinase 4*/genetics , Programmed Cell Death 1 Receptor*/antagonists & inhibitors , Programmed Cell Death 1 Receptor*/metabolism, Cell Proliferation/drug effects ; Apoptosis/drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; Signal Transduction/drug effects ; Animals ; Humans ; Mice ; Cell Line, Tumor ; Xenograft Model Antitumor Assays ; Female |
| Περίληψη: | 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. (Copyright © 2026 The Authors. Published by Elsevier B.V. All rights reserved.) |
| Competing Interests: | Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. |
| Grant Information: | K99 CA286745 United States CA NCI NIH HHS; R00 CA286745 United States CA NCI NIH HHS; R01 CA272906 United States CA NCI NIH HHS |
| Contributed Indexing: | Keywords: Diffuse-type gastric adenocarcinoma; Gastric adenocarcinoma; Small molecule inhibitor; Targeted therapy; Tumor microenvironment |
| Substance Nomenclature: | 0 (SOX9 Transcription Factor) 0 (SOX9 protein, human) EC 2.7.11.22 (Cyclin-Dependent Kinase 4) 0 (Programmed Cell Death 1 Receptor) EC 2.7.11.22 (CDK4 protein, human) |
| Entry Date(s): | Date Created: 20260807 Date Completed: 20260911 Latest Revision: 20260911 |
| Update Code: | 20260912 |
| DOI: | 10.1016/j.canlet.2026.218777 |
| PMID: | 42567470 |
| Βάση Δεδομένων: | MEDLINE |
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