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 & 9 others John 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

25 Citations (Scopus)

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

Fingerprint

Lung Neoplasms
Hypersensitivity
Chemotherapy
Cells
Non-Small Cell Lung Carcinoma
Pharmaceutical Preparations
Recurrence
Drug Therapy
Methylation
Drug Resistance
Histones
Lysine
Up-Regulation
Genes
Cell Line
Survival
taxane
In Vitro Techniques
Therapeutics

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)

Cite this

Taxane-Platin-Resistant Lung Cancers Co-develop Hypersensitivity to JumonjiC Demethylase Inhibitors. / Dalvi, Maithili P.; Wang, Lei; Zhong, Rui; Kollipara, Rahul K.; Park, Hyunsil; Bayo, Juan; Yenerall, Paul; Zhou, Yunyun; Timmons, Brenda C.; Rodriguez-Canales, Jaime; Behrens, Carmen; Mino, Barbara; Villalobos, Pamela; Parra, Edwin R.; Suraokar, Milind; Pataer, Apar; Swisher, Stephen G.; Kalhor, Neda; Bhanu, Natarajan V.; Garcia, Benjamin A.; Heymach, John V.; Coombes, Kevin; Xie, Yang; Girard, Luc; Gazdar, Adi F.; Kittler, Ralf; Wistuba, Ignacio I.; Minna, John D.; Martinez, Elisabeth D.

In: Cell Reports, Vol. 19, No. 8, 23.05.2017, p. 1669-1684.

Research output: Contribution to journalArticle

Dalvi, MP, Wang, L, Zhong, R, Kollipara, RK, Park, H, Bayo, J, Yenerall, P, Zhou, Y, Timmons, BC, Rodriguez-Canales, J, Behrens, C, Mino, B, Villalobos, P, Parra, ER, Suraokar, M, Pataer, A, Swisher, SG, Kalhor, N, Bhanu, NV, Garcia, BA, Heymach, JV, Coombes, K, Xie, Y, Girard, L, Gazdar, AF, Kittler, R, Wistuba, II, Minna, JD & Martinez, ED 2017, 'Taxane-Platin-Resistant Lung Cancers Co-develop Hypersensitivity to JumonjiC Demethylase Inhibitors', Cell Reports, vol. 19, no. 8, pp. 1669-1684. https://doi.org/10.1016/j.celrep.2017.04.077
Dalvi, Maithili P. ; Wang, Lei ; Zhong, Rui ; Kollipara, Rahul K. ; Park, Hyunsil ; Bayo, Juan ; Yenerall, Paul ; Zhou, Yunyun ; Timmons, Brenda C. ; Rodriguez-Canales, Jaime ; Behrens, Carmen ; Mino, Barbara ; Villalobos, Pamela ; Parra, Edwin R. ; Suraokar, Milind ; Pataer, Apar ; Swisher, Stephen G. ; Kalhor, Neda ; Bhanu, Natarajan V. ; Garcia, Benjamin A. ; Heymach, John V. ; Coombes, Kevin ; Xie, Yang ; Girard, Luc ; Gazdar, Adi F. ; Kittler, Ralf ; Wistuba, Ignacio I. ; Minna, John D. ; Martinez, Elisabeth D. / Taxane-Platin-Resistant Lung Cancers Co-develop Hypersensitivity to JumonjiC Demethylase Inhibitors. In: Cell Reports. 2017 ; Vol. 19, No. 8. pp. 1669-1684.
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AU - Dalvi, Maithili P.

AU - Wang, Lei

AU - Zhong, Rui

AU - Kollipara, Rahul K.

AU - Park, Hyunsil

AU - Bayo, Juan

AU - Yenerall, Paul

AU - Zhou, Yunyun

AU - Timmons, Brenda C.

AU - Rodriguez-Canales, Jaime

AU - Behrens, Carmen

AU - Mino, Barbara

AU - Villalobos, Pamela

AU - Parra, Edwin R.

AU - Suraokar, Milind

AU - Pataer, Apar

AU - Swisher, Stephen G.

AU - Kalhor, Neda

AU - Bhanu, Natarajan V.

AU - Garcia, Benjamin A.

AU - Heymach, John V.

AU - Coombes, Kevin

AU - Xie, Yang

AU - Girard, Luc

AU - Gazdar, Adi F.

AU - Kittler, Ralf

AU - Wistuba, Ignacio I.

AU - Minna, John D.

AU - Martinez, Elisabeth D.

PY - 2017/5/23

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N2 - 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.

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KW - KDM

KW - lung cancer

KW - taxane-platin chemotherapy

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