Targeting Taxane-Platin Resistant Lung Cancers with JumonjiC Lysine Demethylase Inhibitors

While taxane-platin standard chemotherapy provides benefit in advanced and localized non-small cell lung cancer (NSCLC), the majority of patients relapse with drug resistant tumors. Mechanisms underlying NSCLC resistance to this standard doublet chemotherapy are still not fully understood, and treatment options for chemoresistant lung tumors are limited. The goals of this work were to establish new preclinical NSCLC models of resistance to taxane-platin doublet chemotherapy, identify mechanisms of resistance, and develop new rational pharmacologic approaches to target drug resistant NSCLCs. Isogenic drug resistant cell lines were established by long-term treatment of chemosensitive, parental NSCLC cell lines (NCI-H1299 and NCI-H1355) with drug on/drug off cycles of paclitaxel + carboplatin doublet chemotherapy given in a clinically relevant 2:3 paclitaxel-to-carboplatin ratio. Total RNA was extracted and microarrays were performed on parental cell lines (used as control) and all developed resistant cell line variants (denoted as T followed by number of chemotherapy cycles). Samples included biological replicates (5 for parental, 2 for each intermediate resistance variant, 3 for the most resistant variant). Subcutaneous xenografts of H1299 parental cell line and the resistant H1299 T18 variant were also profiled by microarrays (3 tumors per group). 35-gene resistance signature was derived from cell lines and xenografts, and evaluated in neoadjuvant treated NSCLC patients to identify a clinically relevant, druggable target. Pharmacological targeting using JumonjiC histone lysine demethylase inhibitors, JIB-04 and GSK-J4, resulted in selective killing of chemoresistant cells over parental cell lines. To reveal mechanistic insights into JumonjiC inhibitor sensitization, H1299 Parental and H1299 T18 resistant cells were each treated with either DMSO, 0.2 µM JIB-04 or 1 µM GSK-J4 for 24 h, and studied by microarrays (2 biological replicates per treatment).