@article{a7ba2395e1db47ffa5ec835ae92a0db2,
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 = "Funding Information: The authors thank current and past members of Minna and Martinez laboratories for assistance, particularly Michael Peyton, Amit Das, Boning Gao, and Nicholas Levonyak. We are thankful to Dr. Michael Roth and Dr. Jerry Shay (UT Southwestern) for helpful discussions. Research reported in this publication was partly funded by the National Cancer Institute (NCI) (grant R01 CA125269 to E.D.M., grant P50CA70907 to J.D.M., and grant P01 CA196539 to B.A.G.), the Department of Defense (grants W81XWH-07-1-0306 and W81XWH-16-1-0129), CPRIT (grants RP160493, RP120717, and RP110708), the Friends of the Cancer Center (E.D.M.), The Welch Foundation (grant I-1878 to E.D.M.), and an LLS Robert Arceci Scholar Award (to B.A.G.). We also recognize the support to UT Southwestern Simmons Cancer Center Shared Resources by the NCI of the National Institutes of Health (grant 5P30CA142543) and to MD Anderson Institutional Tissue Bank, ITBS (grant 2P30CA016672). 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",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "8",
}