Project description:RNA was extracted from myeloma cell lines that were either drug-naïve or resistant to bortezomib or carfilzomib and the transcriptome was characterised using RNA sequencing.
Project description:Expression array data was used to compare parental FGFR3-TACC3 fusion-driven urothelial cell lines with their FGFR inhibitor-resistant derivatives. In this dataset, we include RT112 and RT4 parental cells, RT112 cells acutely treated with PD173074 (24 h), RT112 and RT4 resistant derivatives cultured with drug and their resistant derivatives cultured for four to six passages out of drug.
Project description:The clinical efficacy of bortezomib in multiple myeloma (MM) is limited due to secondary drug resistance driven by clonal evolution and currently available pre-clinical models are inadequate for comprehensive understanding of mechanisms underlying drug resistance. In the present study, we have established and characterized bortezomib-resistant cell lines BR1 and BR2, and identified upregulation of proteasome pathway as the potential mechanism underlying bortezomib resistance. Furthermore, both the cell lines retained sensitivity towards imatinib suggesting the lack of general resistance towards broad classes of inhibitors. Notably, BR1 and BR2 showed increased sensitivity than the parental cell line towards the next-generation proteasome inhibitor carfilzomib, suggesting its utility in treating patients who relapse upon bortezomib treatment. When compared to the wild type cell line, BR1 and BR2 displayed similar sensitivity towards sorafenib and vorinostat, but enhanced sensitivity towards geldanamycin treatment. Taken together, our study identified carfilzomib and HSP90 inhibition as promising therapeutic strategies to overcome bortezomib resistance.
Project description:Modulation of the activity of the ubiquitin-proteasome pathway with the proteasome inhibitor (PI) is an established component of therapy for plasma cell disorders. However, resistance emerges and the mechanism is incompletely understood. We generated carfilzomib-resistant (CR) myeloma cell lines by exposing drug-naive ANBL-6, KAS-6/1, U266, and OPM-2 cells to increasing concentrations of carfilzomib and then performed gene expression profiling (GEP) to identify prominent changes compared to their vehicle-treated counterparts, followed by exploration of the mechanism(s) of proteasome inhibitor resistance.
Project description:Sequencing of olaparib-resistant PEO1 derivatives (C4, C5, C10 and C18) and parental PEO1 (P1 and P2) cells was performed in order to determine mechanisms of acquired resistance in the resistant cell lines. PEO1 parental cell lines were authenticated prior to sequencing. PEO1 parental were confirmed to be BRCA2-mutated (5139C>G). Olaparib PEO1 resistant cells were generated through a step-wise escalation of olaparib (10nM to 8uM olaparib). In olaparib resistant lines an increase canonical Wnt signaling and loss of of non-canonical Wnt signaling was observed.
Project description:Copy number analysis to compare parental colorectal cancer cell lines and their selumetinib-resistant derivatives and identify gene copy changes that might contribute to resistance
Project description:This study investigated mechanisms of acquired resistance to FGFR inhibitor therapy in RAS/RAF–wild-type colorectal cancer (CRC). RNA sequencing (RNA-seq) data from 47 RAS/RAF-wild-type colorectal cancer stem-cell (CRC-SC) spheroid lines previously deposited under GSE205787 were integrated with newly generated RNA-seq data from 31 additional RAS/RAF-wild-type CRC-SC spheroid lines and seven FGFR inhibitor-resistant CRC-SC derivatives. The resistant derivatives were established from parental CRC-SC spheroid lines by continuous exposure to erdafitinib or futibatinib. Comparative transcriptomic analysis between matched parental and resistant lines revealed consistent upregulation of EGFR and downregulation of PTPROt, a truncated isoform of PTPRO, in resistant derivatives. Gene set enrichment analysis further indicated activation of EGFR-related signaling pathways in FGFR inhibitor-resistant spheroids. In addition, the integrated RNA-seq dataset comprising 78 RAS/RAF-wild-type CRC-SC lines was used to validate the inverse correlation between EGFR and PTPRO mRNA expression, supporting the involvement of PTPROt downregulation and EGFR pathway activation in acquired resistance to FGFR inhibition.
Project description:RNA sequencing analysis to compare parental colorectal cancer cell lines and their selumetinib-resistant derivatives and identify expression changes and/or mutations that might contribute to resistance
