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

ZHONG, RUI; BAYO, JUAN; TIMMONS, BRENDA C.; MINO, BARBARA; SURAOKAR, MILIND; WANG, LEI; KALHOR, NEDA; PARK, HYUNSIL; HEYMACH, JOHN V.; ZHOU, YUNYUN; GIRARD, LUC; BEHRENS, CARMEN; DALVI, MAITHILI P.; WISTUBA, IGNACIO I.; PARRA, EDWIN R.; SWISHER, STEPHEN G.; KOLLIPARA, RAHUL K.; GARCIA, BENJAMIN A.; YENERALL, PAUL; XIE, YANG; RODRIGUEZ-CANALES, JAIME; KITTLER, RALF; VILLALOBOS, PAMELA; MARTINEZ, ELISABETH D.; PATAER, APAR; BHANU, NATARAJAN V.; COOMBES, KEVIN; GAZDAR, ADI F.; MINNA, JOHN D.

Cell Reports

Cell Press

Año: 2017 vol. 19 p. 1669 - 1684

2211-1247

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.