Taxane-Platin-Resistant Lung Cancers Co-develop Hypersensitivity to JumonjiC Demethylase Inhibitors

Cell Reports

Kevin Coombes¹  Yunyun Zhou²  Yang Xie²  Rui Zhong²  Neda Kalhor³  Stephen G. Swisher⁴  Apar Pataer⁴  Carmen Behrens⁵  John V. Heymach⁵  Milind Suraokar⁶  Ignacio I. Wistuba⁶  Barbara Mino⁶  Pamela Villalobos⁶  Edwin R. Parra⁶  Jaime Rodriguez-Canales⁶  Natarajan V. Bhanu⁷  Benjamin A. Garcia⁷  Rahul K. Kollipara⁸  John D. Minna⁹  Paul Yenerall⁹  Adi F. Gazdar⁹  Juan Bayo⁹  Luc Girard⁹  Hyunsil Park⁹  Brenda C. Timmons⁹  Lei Wang⁹  Maithili P. Dalvi⁹  Elisabeth D. Martinez⁹  Ralf Kittler^1,10 

[1] Department of Biomedical Informatics, The Ohio State University College of Medicine, Columbus, OH 43210, USA;Department of Clinical Science, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA;Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;Epigenetics Program, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA;Eugene McDermott Center for Human Growth and Development, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA;Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA;Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA;

关键词: Jumonji demethylases;    JIB-04;    GSK-J4;    drug resistance;    taxane-platin chemotherapy;    KDM;    demethylase inhibitors;    histone methylation;    histone demethylases;    lung cancer;   

DOI  :  10.1016/j.celrep.2017.04.077

来源: DOAJ

【 摘 要 】

Although non-small cell lung cancer (NSCLC) patients benefit from standard taxane-platin chemotherapy, many relapse, developing drug resistance. We established preclinical taxane-platin-chemoresistance models and identified a 35-gene resistance signature, which was associated with poor recurrence-free survival in neoadjuvant-treated NSCLC patients and included upregulation of the JumonjiC lysine demethylase KDM3B. In fact, multi-drug-resistant cells progressively increased the expression of many JumonjiC demethylases, had altered histone methylation, and, importantly, showed hypersensitivity to JumonjiC inhibitors in vitro and in vivo. Increasing taxane-platin resistance in progressive cell line series was accompanied by progressive sensitization to JIB-04 and GSK-J4. These JumonjiC inhibitors partly reversed deregulated transcriptional programs, prevented the emergence of drug-tolerant colonies from chemo-naive cells, and synergized with standard chemotherapy in vitro and in vivo. Our findings reveal JumonjiC inhibitors as promising therapies for targeting taxane-platin-chemoresistant NSCLCs.

【 授权许可】

Unknown