gsk-j4 and Lung-Neoplasms

Topics: Animals; Benzazepines; Bone Neoplasms; Cell Line, Tumor; Cell Movement; Gene Knockdown Techniques; Histone Code; Humans; Jumonji Domain-Containing Histone Demethylases; L-Lactate Dehydrogenase; Lung Neoplasms; Mice; Mice, Nude; Molecular Targeted Therapy; Osteosarcoma; Precision Medicine; Prognosis; Pyrimidines; Up-Regulation; Xenograft Model Antitumor Assays

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.

Topics: Aminopyridines; Animals; Antineoplastic Agents; Benzazepines; Bridged-Ring Compounds; Carboplatin; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Disease-Free Survival; Drug Resistance, Neoplasm; Enzyme Inhibitors; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Histones; Humans; Hydrazones; Jumonji Domain-Containing Histone Demethylases; Lung Neoplasms; Methylation; Mice; Neoadjuvant Therapy; Pyrimidines; Taxoids; Transcription, Genetic

Malignant pleural mesothelioma (MPM) is a rare aggressive cancer of the pleura primarily associated with prior exposure to asbestos. The current standard of care for patients suffering from MPM is a combination of cisplatin and pemetrexed (or alternatively cisplatin and raltitrexed). Most patients, however, die within 24 months of diagnosis. New therapies are therefore urgently required for this disease. Inflammation is thought to be a key element in the pathogenesis of MPM, and recently Kdm6 family members (Kdm6a and Kdm6b) have been identified as playing important roles in inflammatory processes. As such these genes could potentially represent novel candidate targets for intervention in MPM. Using RT-PCR we examined the expression of Kdm6aA and Kdm6b in a panel of MPM cell lines and in a cohort of snap-frozen patient samples isolated at surgery comprising benign, epithelial, biphasic and sarcomatoid histologies. Both Kdm6a and Kdm6b were found to be significantly overexpressed in MPM at the mRNA level. However, tests examining if targeting therapeutically Kdm6a/b using a specific small molecule inhibitor (GSK-J4) was potentially useful for treating MPM, revealed that anti-proliferative activity was higher at lower drug concentrations in cell lines derived from normal mesothelial cells compared to those derived from malignant cells. Treatments with GSK-J4 were found to be associated with the induction of apoptosis and increased expression of pro-inflammatory cytokines. As such our results demonstrate that whilst members of the Kdm6 family are overexpressed in MPM they may not be suitable candidates for therapy and may elicit a cytokine storm.

Topics: Apoptosis; Benzazepines; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cisplatin; Cytokines; Gene Expression Regulation, Neoplastic; Histone Demethylases; Humans; Jumonji Domain-Containing Histone Demethylases; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant; Nuclear Proteins; Pemetrexed; Pyrimidines

GSKJ4, an H3K27 demethylase inhibitor, reportedly exhibits antitumor activity against specific cancers harboring genetic alterations in genes encoding chromatin modulators. However, its potential as an anticancer agent against human cancers not associated with such genetic alterations, including non-small cell lung cancer (NSCLC), remains unknown.. The effect of GSKJ4 on the growth of three NSCLC cell lines and normal lung fibroblasts was investigated using the WST-8, dye exclusion, and colony formation assays.. GSKJ4, alone and in combination with an anti-diabetic drug metformin, induced cell death and inhibited the growth of NSCLC cell lines efficiently at concentrations non-toxic to normal cells, irrespective of their genetic backgrounds (mutations in the KRAS, TP53 and EGFR genes) and also of their resistance to cisplatin and paclitaxel.. GSKJ4, being a promising anticancer agent for NSCLC, may be effective against a wider spectrum of cancers than previously thought.

Topics: Benzazepines; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Enzyme Inhibitors; Humans; Lung Neoplasms; Metformin; Pyrimidines