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

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 journal › Article › peer-review

72 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 language	English (US)
Pages (from-to)	1669-1684
Number of pages	16
Journal	Cell Reports
Volume	19
Issue number	8
DOIs	https://doi.org/10.1016/j.celrep.2017.04.077
State	Published - May 23 2017
Externally published	Yes

Keywords

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

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2017.04.077

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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

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

@article{cd4bc909d583437cbe6381c9f6a5ae0b,

title = "Taxane-Platin-Resistant Lung Cancers Co-develop Hypersensitivity to JumonjiC Demethylase Inhibitors",

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",

author = "Dalvi, {Maithili P.} and Lei Wang and Rui Zhong and Kollipara, {Rahul K.} and Hyunsil Park and Juan Bayo and Paul Yenerall and Yunyun Zhou and Timmons, {Brenda C.} and Jaime Rodriguez-Canales and Carmen Behrens and Barbara Mino and Pamela Villalobos and Parra, {Edwin R.} and Milind Suraokar and Apar Pataer and Swisher, {Stephen G.} and Neda Kalhor and Bhanu, {Natarajan V.} and Garcia, {Benjamin A.} and Heymach, {John V.} and Kevin Coombes and Yang Xie and Luc Girard and Gazdar, {Adi F.} and Ralf Kittler and Wistuba, {Ignacio I.} and Minna, {John D.} and Martinez, {Elisabeth D.}",

note = "Publisher Copyright: {\textcopyright} 2017 The Authors",

year = "2017",

month = may,

day = "23",

doi = "10.1016/j.celrep.2017.04.077",

language = "English (US)",

volume = "19",

pages = "1669--1684",

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TY - JOUR

T1 - Taxane-Platin-Resistant Lung Cancers Co-develop Hypersensitivity to JumonjiC Demethylase Inhibitors

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

Y1 - 2017/5/23

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.

AB - 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.

KW - GSK-J4

KW - JIB-04

KW - Jumonji demethylases

KW - KDM

KW - demethylase inhibitors

KW - drug resistance

KW - histone demethylases

KW - histone methylation

KW - lung cancer

KW - taxane-platin chemotherapy

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UR - http://www.scopus.com/inward/citedby.url?scp=85019727872&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2017.04.077

DO - 10.1016/j.celrep.2017.04.077

M3 - Article

C2 - 28538184

AN - SCOPUS:85019727872

SN - 2211-1247

VL - 19

SP - 1669

EP - 1684

JO - Cell Reports

JF - Cell Reports

IS - 8

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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