Cell Reports (May 2017)
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
Affiliations
- Maithili P. Dalvi
- Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Lei Wang
- Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Rui Zhong
- Department of Clinical Science, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Rahul K. Kollipara
- Eugene McDermott Center for Human Growth and Development, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Hyunsil Park
- Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Juan Bayo
- Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Paul Yenerall
- Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Yunyun Zhou
- Department of Clinical Science, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Brenda C. Timmons
- Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Jaime Rodriguez-Canales
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Carmen Behrens
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Barbara Mino
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Pamela Villalobos
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Edwin R. Parra
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Milind Suraokar
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Apar Pataer
- Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Stephen G. Swisher
- Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Neda Kalhor
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Natarajan V. Bhanu
- Epigenetics Program, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Benjamin A. Garcia
- Epigenetics Program, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- John V. Heymach
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Kevin Coombes
- Department of Biomedical Informatics, The Ohio State University College of Medicine, Columbus, OH 43210, USA
- Yang Xie
- Department of Clinical Science, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Luc Girard
- Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Adi F. Gazdar
- Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Ralf Kittler
- Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Ignacio I. Wistuba
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- John D. Minna
- Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Elisabeth D. Martinez
- Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- DOI
- https://doi.org/10.1016/j.celrep.2017.04.077
- Journal volume & issue
-
Vol. 19,
no. 8
pp. 1669 – 1684
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
- Jumonji demethylases
- JIB-04
- GSK-J4
- drug resistance
- taxane-platin chemotherapy
- KDM
- demethylase inhibitors
- histone methylation
- histone demethylases
- lung cancer
