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

• DOI: 10.1016/j.celrep.2017.04.077
• Publication Date: 2017-05-23T18:02:48Z
• Authors: Maithili P. Dalvi; Lei Wang; Rui Zhong; Rahul K. Kollipara; Hyunsil Park; Juan Bayo; Paul Yenerall; Yunyun Zhou; Brenda C. Timmons; Jaime Rodriguez-C...; Carmen Behrens; Barbara Mino; Pamela Villalobos; Edwin R. Parra; Milind Suraokar; Apar Pataer; Stephen G. Swisher; Neda Kalhor; Natarajan V. Bhanu; Benjamin A. Garcia; John V. Heymach; Kevin Coombes; Yang Xie; Luc Girard; Adi F. Gazdar; Ralf Kittler; Ignacio I. Wistuba; John D. Minna; Elisabeth D. Mart...
• Keywords: Bridged-Ring Compounds; 0301 basic medicine; Jumonji Domain-Containing Histone Demethylases; Lung Neoplasms; QH301-705.5; NSCLCS; Aminopyridines; Antineoplastic Agents; Methylation; Disease-Free Survival; taxane-platin chemotherapy; KDM; Carboplatin; histone demethylases; Histones; Mice; 03 medical and health sciences; GSK-J4; https://purl.org/becyt/ford/3.4; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Animals; Humans; https://purl.org/becyt/ford/3; histone methylation; Biology (General); Enzyme Inhibitors; Jumonji demethylases; drug resistance; Gene Expression Profiling; Hydrazones; LUNG CANCER; Benzazepines; 3. Good health; DRUG RESISTANCE; Gene Expression Regulation, Neoplastic; lung cancer; Drug Resistance, Neoplasm; JIB-04; demethylase inhibitors

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.