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

Abstract

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.

• Authors: Maithili P Dalvi, Lei Wang, Rui Zhong, Rahul K Kollipara, Hyunsil Park, Juan Bayo, Paul Yenerall, Yunyun Zhou, Brenda C Timmons, Jaime Rodriguez-Canales, 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 Martinez
• Journal: Cell reports (Cell Rep) Vol. 19 Issue 8 Pg. 1669-1684 (05 23 2017) ISSN: 2211-1247 [Electronic] United States
• PMID: 28538184 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Aminopyridines
• Antineoplastic Agents
• Benzazepines
• Bridged-Ring Compounds
• Enzyme Inhibitors
• GSK-J4
• Histones
• Hydrazones
• JIB-04
• Pyrimidines
• Taxoids
• taxane
• Carboplatin
• Jumonji Domain-Containing Histone Demethylases
• KDM3B protein, human

Topics

• Aminopyridines (adverse effects, pharmacology, therapeutic use)
• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Benzazepines (adverse effects, pharmacology, therapeutic use)
• Bridged-Ring Compounds (pharmacology, therapeutic use)
• Carboplatin (pharmacology, therapeutic use)
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics, pathology)
• Cell Line, Tumor
• Disease-Free Survival
• Drug Resistance, Neoplasm (drug effects, genetics)
• Enzyme Inhibitors (pharmacology, therapeutic use)
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic (drug effects)
• Histones (metabolism)
• Humans
• Hydrazones (adverse effects, pharmacology, therapeutic use)
• Jumonji Domain-Containing Histone Demethylases (antagonists & inhibitors, metabolism)
• Lung Neoplasms (drug therapy, genetics, pathology)
• Methylation
• Mice
• Neoadjuvant Therapy
• Pyrimidines (adverse effects, pharmacology, therapeutic use)
• Taxoids (pharmacology, therapeutic use)
• Transcription, Genetic (drug effects)