Project description:Idelalisib was the first-in-class PI3Kδ inhibitor and additional compounds are undergoing clinical investigation. To identify modalities to overcome resistance to these agents, we have developed idelalisib-resistant model derived from marginal zone lymphoma cell line (VL51). Cells were kept under idelalisib until acquisition of resistance (VL51-RER) or with no drug (parental). In this experiment we identified the modulated genes between the resistant cell line and the parental counterpart (sensitive to the drug) We invastigated the transcriptomic profiles of parental K1718 B-cell lymphoma cell lines and the same cell line made resistant to Idelalisib. in addition two B-Cells (SUDHL2 and SUDHL4) are made resistant to IMGN529 (Naratuximab emtansine) an antibody-drug conjugate (ADC) incorporating an anti-CD37 monoclonal antibody conjugated to the maytansinoid DM1 as payload.
Project description:BCR pathway inhibitors idelalisib and ibrutinib are the first small molecule targeted agents for B-cell malignancies. In spite of encouraging response rates in various forms of B cell diseases, patients will eventually develop relapse due to the emergence of resistant cells. To better identify the possible mechanisms of resistance we developed and characterized idelalisib- and ibrutinib-resistant variants of the human non Hodgkin’s lymphoma cell lines DoHH2 and Daudi. These resistant variants displayed a cross-resistance profile limited to PI3K inhibitors, BTK inhibitors and a SYK inhibitor but not to unrelated agents. A number of alterations were observed in the resistant lines, including a strong reduction of the Akt3 protein. Resistant lines tended to express larger amounts of CD38 and CD52 on their cell membrane and were found to display enhanced sensitivity to anti-CD38 antibodies. These results identify potential novel mechanisms of resistance to idelalisib and ibrutinib and raise the possibility that cells resistant to BCR pathway inhibitors might possess enhanced sensitivity to anti-CD38 antibodies.
Project description:RNAseq profile of TMD8 cell lines resistant to Idelalisib treatment. Idelalisib resistant TMD8 cells were generated by continuous passage in the presence of 1 μM idelalisib for 8 weeks until stable resistance to idelalisib was established. Parallel cultures were grown in the presence of 0.1% DMSO as passage-matched, drug-sensitive control lines. Sensitive and resistant TMD8 cells were clonally isolated through two rounds of single cell limiting dilution
Project description:RNA sequencing data of paired parental and therapy resistant cancer cell lines. Parental cell lines are mostly established cell lines. Resistant cell lines were obtained through long term exposure of the parental cells to gradually increasing doses of cancer therapies. Samples include 7 parental and 10 derived resistant cell lines. Our aim was to assess whether the resistant cells had undergone Epithelial to Mesenchymal Transition upon resistance acquisition.
Project description:Genome wide DNA methylation profiling of paired parental and therapy resistant cancer cell lines. Parental cell lines are mostly established cell lines. Resistant cell lines were obtained through long term exposure of the parental cells to gradually increasing doses of cancer therapies. The Illumina Infinium 450k and EPIC Human DNA methylation Beadchips were used to obtain DNA methylation profiles across approximately 450,000 or 850,000 CpGs from the cells. Samples include 7 parental and 10 derived resistant cell lines.
Project description:Genome wide DNA methylation profiling of paired parental and therapy resistant cancer cell lines. Parental cell lines are mostly established cell lines. Resistant cell lines were obtained through long term exposure of the parental cells to gradually increasing doses of cancer therapies. Followig the published TAB-sequencing protocol, the Illumina Infinium 450K or EPIC Human DNA methylation Beadchips were used to obtain DNA hydroxymethylation profiles across approximately 450,000 or 850,000 CpGs from the cells. Samples include 5 parental and 6 derived resistant cell lines.
Project description:microRNA and mRNA profiling was conducted for parental cell lines and cell lines resistant to trifluridine in 3 colorectal cell lines (DLD-1, HCT-116, RKO). We hypothesized that a detailed comparison between miRNA and mRNA expression might reveal the mechanism for acquired resistant to trifluridine in colorectal cancer.
Project description:microRNA and mRNA profiling was conducted for parental cell lines and cell lines resistant to trifluridine in 3 colorectal cell lines (DLD-1, HCT-116, RKO). We hypothesized that a detailed comparison between miRNA and mRNA expression might reveal the mechanism for acquired resistant to trifluridine in colorectal cancer.