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. GarciaJohn V. Heymach, Kevin Coombes, Yang Xie, Luc Girard, Adi F. Gazdar, Ralf Kittler, Ignacio I. Wistuba, John D. Minna, Elisabeth D. Martinez

Research output: Contribution to journalArticle

32 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1669-1684
Number of pages16
JournalCell Reports
Volume19
Issue number8
DOIs
StatePublished - May 23 2017

Keywords

  • demethylase inhibitors
  • drug resistance
  • GSK-J4
  • histone demethylases
  • histone methylation
  • JIB-04
  • Jumonji demethylases
  • KDM
  • lung cancer
  • taxane-platin chemotherapy

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Dalvi, M. P., Wang, L., Zhong, R., Kollipara, R. K., Park, H., Bayo, J., Yenerall, P., Zhou, Y., Timmons, B. C., Rodriguez-Canales, J., Behrens, C., Mino, B., Villalobos, P., Parra, E. R., Suraokar, M., Pataer, A., Swisher, S. G., Kalhor, N., Bhanu, N. V., ... Martinez, E. D. (2017). Taxane-Platin-Resistant Lung Cancers Co-develop Hypersensitivity to JumonjiC Demethylase Inhibitors. Cell Reports, 19(8), 1669-1684. https://doi.org/10.1016/j.celrep.2017.04.077