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Telomerase-mediated Strategy for Overcoming Non-Small Cell Lung Cancer Targeted Therapy and Multi-drug Chemotherapy Resistance

ABSTRACT: Standard and targeted therapies almost universally fail due to tumor heterogeneity/plasticity leading to intrinsic or acquired drug resistance. We used the telomerase substrate precursor 6-thio-2’-deoxyguanosine (6-thio-dG) to target telomerase-expressing targeted therapy and platin-doublet chemotherapy resistant cells. We observed that erlotinib, paclitaxel/carboplatin and gemcitabine/cisplatin resistant cells are sensitive to 6-thio-dG in xenograft, syngeneic immunocompetent and genetically engineered mouse models. We also show sensitivity to 6-thio-dG on a large panel of non-small cell lung cancer cell lines (73 of 77). The 4 resistant NSCLC lines clustered together, providing a molecular signature for patients that may not respond to 6-thio-dG. We find SLC43A3 as a top candidate in this molecular signature. Thus, 6-thio-dG may prolong disease control of therapy-resistant lung cancer patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE109821 | GEO | 2018/01/30

REPOSITORIES: GEO

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Project description:Although therapy responsiveness to therapy in Burkitt lymphoma (BL) is high, relapsed disease and and chemoresistance remain a clinical challenge, and complete mechanisms underlying BL chemoresistance and how it can be circumvented is yet to be fully elucidated. In this study we present data showing that chymotrypsin-like serine proteases inhibitor Nα-tosyl-L-phenylalanine chloromethylketone (TPCK) and specific NF-κB inhibitor Bay-11 7082 can induce caspase-independent apoptosis in chemoresistant BL cells. We also demonstrate that both TPCK and Bay-11 7082-treatment leads to decreased NF-κB nuclear activity and that this is associated with sensitization of chemoresistant Burkitt lymphoma cells. Furthermore we investigated global transcriptional changes induced by Bay-11 7082 and TPCK in the DG-75 and Raji cell lines, respectively, by microarray analysis using Illumina BeadChips. TPCK-treatment of Raji and DG-75 cells resulted in 59 and 21 differently expressed genes, respectively, while Bay-11-treated Raji and DG-75 cells displayed 1403 and 8 differently expressed genes, respectively. Gene Ontology (GO) categorization confirmed enrichment of multiple GOs in Bay 11-treated Raji and DG-75 cells. Fifty percent of the 61 categories in Raji cells were categories sorting under Biological Processes and represented mostly increased gene expression. In DG-75 cells Bay-11 7082 induced significant gene ontology enrichment in only two categories, where the increased/decreased ratio was 1:1. Further unsupervised and supervised bioinformatics processing by Ingenuity Pathway Analysis indicated significant networks in response to TPCK and Bay 11 respectively, including association to NF-κB. Bay-11 7082 demonstrated deregulated NF-κB related members of receptor mediated cell death signaling, i.e TRAF2 and TRADD, as well as deregulated members of the NF-κB signaling pathway from the cytoplasmic compartment, i.e RELB, in Raji cells. Comparably NF-κB network analysis of Raji- and DG-75 cells treated with Bay-11 7082 and Raji cells treated with TPCK demonstrated deregulation of NF-κB target genes CD69 and IL8. These data indicates that NF-kB may play a role in overcoming chemoresistance in BL cells with defective classical apoptosis signaling. NF-κB network analysis of Raji- and DG-75 cells treated with Bay-11 7082 and Raji cells treated with TPCK

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Telomerase-mediated Strategy for Overcoming Non-Small Cell Lung Cancer Targeted Therapy and Multi-drug Chemotherapy Resistance

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