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

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

doi:10.1016/j.celrep.2017.04.077

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

Cell Rep. 2017 May 23;19(8):1669-1684. doi: 10.1016/j.celrep.2017.04.077.

Authors

Maithili P Dalvi¹, Lei Wang², Rui Zhong³, Rahul K Kollipara⁴, Hyunsil Park⁵, Juan Bayo², Paul Yenerall⁶, Yunyun Zhou³, Brenda C Timmons¹, Jaime Rodriguez-Canales⁷, Carmen Behrens⁸, Barbara Mino⁷, Pamela Villalobos⁷, Edwin R Parra⁷, Milind Suraokar⁷, Apar Pataer⁹, Stephen G Swisher⁹, Neda Kalhor¹⁰, Natarajan V Bhanu¹¹, Benjamin A Garcia¹¹, John V Heymach⁸, Kevin Coombes¹², Yang Xie³, Luc Girard², Adi F Gazdar¹, Ralf Kittler¹³, Ignacio I Wistuba¹⁴, John D Minna¹⁵, Elisabeth D Martinez¹⁶

Affiliations

¹ 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.
² Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
³ Department of Clinical Science, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
⁴ Eugene McDermott Center for Human Growth and Development, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
⁵ Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
⁶ 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; Eugene McDermott Center for Human Growth and Development, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
⁷ Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁸ Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁹ Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁰ Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹¹ Epigenetics Program, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
¹² Department of Biomedical Informatics, The Ohio State University College of Medicine, Columbus, OH 43210, USA.
¹³ Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Eugene McDermott Center for Human Growth and Development, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
¹⁴ Department of Translational Molecular Pathology, 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.
¹⁵ 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; Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
¹⁶ 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; Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: [email protected].

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.

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

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

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

Substances

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding