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

Publication date: 23 May 2017
Source:Cell Reports, Volume 19, Issue 8
Author(s): 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
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.

Graphical abstract

Teaser

Taxane-platin chemotherapy for non-small cell lung cancer (NSCLC) is beneficial, yet most tumors become drug resistant. Dalvi et al. find upregulation of JumonjiC demethylases in clinical NSCLC samples and preclinical models of resistance. Resistant cells and tumors show hypersensitivity to JumonjiC inhibitors, suggesting a therapeutic opportunity for targeting taxane-platin resistance.


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