Targeting Taxane-Platin Resistant Non-Small Cell Lung Cancers with Jumonji C Histone Lysine Demethylase Inhibitors




Dalvi, Maithili Prafulla

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Taxane-platin doublet therapy provides benefit as front-line chemotherapy in advanced and localized non-small cell lung cancer (NSCLC); however the majority of patients relapse with drug resistant tumors. Novel therapies for targeting drug refractory NSCLC tumors are urgently needed. The goals of this dissertation project were to establish pre-clinical models of NSCLC resistance to standard chemotherapy, identify clinically relevant resistance mechanisms, and develop new rational pharmacologic approaches for overcoming taxane-platin drug resistance in lung cancer. Pre-clinical resistance models were established by treating chemo-sensitive human NSCLC cell lines with increasing cycles of paclitaxel + carboplatin therapy, given in clinically relevant dose ratios. Progression of resistance was monitored by comparing drug response phenotypes, and by investigating genome-wide mRNA expression profiling. Xenografts of parental cells and resistant variants were developed to identify differential gene expression changes in vivo. Pre-clinical mRNA expression signature for taxane + platin resistance was developed and evaluated on a molecularly and clinically annotated dataset of 65 neoadjuvant treated NSCLC patient tumors, to identify therapeutic targets. NSCLC cell lines NCI-H1299 and NCI-H1355 treated for 16-18 cycles with paclitaxel + carboplatin showed progressive increases in drug resistance, eventually achieving >50 fold shift in IC50. Resistant tumors showed reduced response to taxane-platin chemotherapy in vivo. Resistant cell line variants expressed multi-drug resistance transporter and exhibited cross-resistance to several chemotherapies. But, resistance was partially reversible upon drug-free culturing, suggesting transient mechanisms. To systematically identify gene expression changes associated with drug resistance, a linear regression model was fitted on microarray datasets of progressively resistant H1299 and H1355 variants. Overlap between cell line models and in vivo xenograft expression yielded a 35-gene resistance signature. This pre-clinical resistance signature clustered the cohort of 65 neoadjuvant treated NSCLC patients into two distinct groups that showed significant differences in cancer recurrence-free survival. Cox multivariate regression identified the JumonjiC histone lysine demethylase KDM3B as the most significant contributor to poor recurrence-free prognosis. Taxane-platin resistant cell line variants showed up-regulation of several JumonjiC histone lysine demethylases and exhibited globally reduced levels of histone H3K27 trimethylation. Resistant variants showed increased sensitivity to JumonjiC demethylase inhibitors, JIB-04 and GSK-J4, in vitro and in vivo. JumonjiC inhibitors synergistically inhibited colony formation from paclitaxel + carboplatin resistant variants, and also prevented the emergence of drug-tolerant clones from chemo-sensitive, parental cell lines. In conclusion, these studies reveal up-regulation of JumonjiC lysine demethylases during the development of drug resistance and define JumonjiC demethylase inhibitors as a new therapeutic approach for overcoming taxane-platin drug resistance in NSCLCs.

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