Project description:To examine the CHST11 controls transcriptome in NSCLC cells, we preformed the Affymetrix Human Genome U133 Plus 2.0 Array with empty vector or CHST11 expression vector in A-549 or NCI-H358 cells Then the transcriptome were compared with each other to see the CHST11-regulating gene in NSCLC cells
Project description:NCI-H358 is a KRAS G12C-mutant non-small lung cancer cell line known to be sensitive to KRAS G12C-inhibitor sotorasib. Here, we aimed to develop sotorasib resistance in H358 and interrogate the resulting sotorasib-resistant cell line (H358-R). The H358-R cell line was created by continuous culturing of the H358 cells in sotorasib (250 nM) until cells grew readily under sotorasib pressure (approximately 2 months). We then performed RNA-seq of the resulting sotorasib-resistant cell line (H358-R) with and without sotorasib pressure, compared to the parental sensitive cell line control (H358). KRAS gene expression level was found to be increased in the sotorasib-resistant line compared with the parental cells, likely representing a mechanism of resistance. The increased KRAS expression level in the resistant cell line was maintained under sotorasib pressure.
Project description:Paradoxical RAF activation by chemical RAF inhibitors (RAFi) is a well-understood ‘on-target’ biological and clinical phenomenon. In this experiment, we profile the time-dependent gene expression changes that are specific to dabrafenib, selumetinib and the combination of dabrafenib plus selumetinib.
Project description:Class 2 and 3 non-V600E BRAF mutations are oncogenic drivers in many cancer types. Currently, there are no established targeted therapies with proven efficacy for cancers with non-V600E BRAF mutations. We developed the investigator-initiated, Phase II BEAVER clinical trial (NCT03839342) to evaluate the efficacy of BRAF and MEK inhibitors in patients with non-V600E BRAF mutations. The best objective response rate was 14% (3/21). By analyzing genomic data from patient tumors, circulating tumor DNA (ctDNA), patient-derived xenograft (PDX) models generated from enrolled patients, and Class 2 & 3 BRAF mutant cell lines, we discovered MAPK-dependent and independent mechanisms of resistance to BRAF/MEK inhibition. These mechanisms included the acquisition of new mutations in NRAS, MAP2K1, RAF1, and RB in ctDNA at the time of disease progression. CDK4/6 and SHP2 were identified as mediators of intrinsic resistance to BRAF/MEK inhibition in Class 2 & 3 BRAF mutant tumors. Therapeutic strategies combining CDK4/6 or SHP2 inhibitors with BRAF/MEK inhibitors were more effective than BRAF/MEK inhibitors alone in these cancers.
Project description:To determine the difference of gene expression profile in epithelial and mesenchymal KRAS mutant lung cancers, epithelial NCI-H358 cells were treated with TGFβ1 (4 ng/mL) or PBS for 14 days in order to induce epithelial to mesenchymal transition (EMT). Gene expression was determined in NCI-H358 cells before and after EMT induction. In addition, in order to investigate the effect of a MEK inhibitor trametinib on gene expression, mesenchymal NCI-H1792 cells were treated with 50 nM trametinib for 48 hours. Gene expression of H1792 cells for pre- and post-trametinib treatement was determined.
Project description:This study contains 4 exomes of A375, parental, BRAF resistant population, MEK resistant population and a BRAF/MEK resistant population
Project description:To analyse the RNA expression differences between melanoma tumour samples treated with BRAF and MEK-inhibitors at different time points
Project description:Transcriptional profiles of formalin-fixed-paraffin-embedded melanoma metastases including pre-treatment (PRE) and post-treatment (POST) specimens from 50 patients treated with BRAF inhibitors or with BRAF and MEK inhibitors
Project description:This study used microarray expression analysis to identify global changes in transcript alteration in response to MEK inhibition. Genes under ERK control were identified in a panel of V600E BRAF and RTK-activated tumor cells and xenografts, using short-term inhibition of ERK activity using the MEK inhibitor PD0325901 (Pfizer). This SuperSeries is composed of the SubSeries listed below.