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: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
Project description:Anti-tumor effect of the combination between 5-FU and selumetinib was treatment schedule-dependent in BRAF or KRAS mutant CRC cells. Treatment of 5-FU for 2 days followed by selumetinib for another 2 days exhibited synergism for cell viability, whereas single or reversely combined treatment showed antagonism Microarray analysis revealed the distinct groups of genes underlying the efficacy for schedule-dependent treatment.
Project description:Here, we investigate gene expression response of the BRAFV600E mutant cell line COLO205 to the MEK inhibitor selumetinib / AZD6244 / ARRY-142886. Although selumetinib causes long term G1 arrest, we observe cells stochastically entering the cell cycle without re-activation of ERK and initiation of a normal proliferative gene expression programme. Genes encoding DNA replication and repair factors are downregulated during G1 arrest, but many of these are transiently induced when cells escaping arrest enter S and G2. Nonetheless, mRNAs encoding key DNA replication factors including the MCM replicative helicase complex, PCNA and TIPIN remain at very low abundance.
Project description:Here, we investigate gene expression response of the BRAFV600E mutant cell line COLO205 to the MEK inhibitor selumetinib / AZD6244 / ARRY-142886. Although selumetinib causes long term G1 arrest, we observe cells stochastically entering the cell cycle without re-activation of ERK and initiation of a normal proliferative gene expression programme. Genes encoding DNA replication and repair factors are downregulated during G1 arrest, but many of these are transiently induced when cells escaping arrest enter S and G2. Nonetheless, mRNAs encoding key DNA replication factors including the MCM replicative helicase complex, PCNA and TIPIN remain at very low abundance.
Project description:CGH profiling of M249 melanoma cell line treated with step-wise increasing Vemurafenib and Selumetinib to develop resistance (VSR). The resistance mechanims was through BRAF amplification in double minute (DM) format. The control cell line is untreated M249.
Project description:MDA231, BT549, and SUM159PT basal-like breast cancer cell lines were transfected with non-targeting siRNA (siCONTROL), siRNA targeting DUSP4 (siDUSP4), or siCONTROL + 4 or 24 hr of 1uM selumetinib. Cells were harvested at 96 hr post-siRNA transfection. Data were Log2 RMA normalized. We sought to identify changes in gene expression after MEK inhibition, or after loss of DUSP4 function in breast cancer cell lines.
Project description:Here we apply single cell bisulfite sequencing to detect epigenetic and genetic changes that occur in BRAF V600E cells that escape G1 arrest and return to the cell cycle during treatment with the MEK inhibitor selumetinib. We detect no major changes in DNA methylation, but find that cells in G2 are enriched in large amplifications and deletions that we ascribe to abnormal mitotic chromosome segregation.
Project description:MDA231, BT549, and SUM159PT basal-like breast cancer cell lines were transfected with non-targeting siRNA (siCONTROL), siRNA targeting DUSP4 (siDUSP4), or siCONTROL + 4 or 24 hr of 1uM selumetinib. Cells were harvested at 96 hr post-siRNA transfection. Data were Log2 RMA normalized.
Project description:KRAS is one of the driver oncogenes in non-small cell lung cancer (NSCLC), but remains refractory to current modalities of targeted pathway inhibition, which include inhibiting downstream kinase MEK to circumvent KRAS activation. Here, we show that pulsatile, rather than continuous, treatment with MEK inhibitors (MEKis) maintains T cell activation and better control tumor growth and survival. We used microarrays to examine the MAPK signaling pathway suppression from tumor lungs of KRASG12C GEMM after continuous vs. pulsatile treatment of selumetinib.
