Project description:In this study, we compared expression profiles between luciferase-expressing pancreatic cancer cell line MIA/luc with and without MEK inhibitor PD325901treatment in vivo.
Project description:This research trial is testing a combination of two experimental drugs, MSC1936369B (Mitogen-activated protein extracellular signal-regulated kinase (MEK) Inhibitor) and SAR245409 (Phosphatidylinositol 3-kinase (Pi3K)/Mammalian Target of Rapamycin (mTOR) inhibitor), in the treatment of locally advanced or metastatic solid tumors. The primary purpose of the study is to determine the maximum tolerated dose of the drug combination.
Project description:Mitogen-activated protein kinases (MEK 1/2) are central components of the RAS signaling pathway and attractive targets for cancer therapy. However, PIK3CA mutation, which commonly co-occurs with KRAS mutation, offered resistance to MEK inhibitor through activation of PI3K-AKT signaling. We identified a gene that cooperates with MEK inhibitors to forcefully treat PIK3CA mutant colon cancer cells. -catenin, a key molecule of the WNT pathway, emerged as a candidate by protein/Ab Chip array. MEK inhibitor treatment led to a decrease in -catenin in PIK3CA wild-type colon cancer cells but not in PIK3CA mutant colon cancer cells. Tumor regression was promoted by a combination of MEK inhibitor and NVP-TNS656, which targets the WNT pathway. Furthermore, combined inhibition of MEK and -catenin by NVP-TNS656 promoted tumor regression in colon cancer patient-derived xenograft (PDX) models expressing mutant PIK3CA. Taken together, we propose that inhibition of the WNT pathway, particularly -catenin, may bypass resistance to MEK inhibitor in human PIK3CA mutant colon cancer. Additionally, -catenin is a potential PD marker of MEK inhibitor resistance. In the study, we identified and evaluated biomarker for response to MEK inhibitor on colon cancer cells.
Project description:Comparison of the changes in the gene expression profile of cells in which NF1 has been knocked down by RNAi in the presence/absence of the MEK inhibitor UO126 Experiment Overall Design: Primary Rat Schwann cells were transiently transfected with either scrambled (control) or NF1 RNAi oligonucleotides in the presence/absence of the MEK inhibitor UO126. Total RNA was then harvested 48 hours post-transfection. Three independent biological replicates were analysed.
Project description:Mitogen-activated protein kinases (MEK 1/2) are central components of the RAS signaling pathway and attractive targets for cancer therapy. However, PIK3CA mutation, which commonly co-occurs with KRAS mutation, offered resistance to MEK inhibitor through activation of PI3K-AKT signaling. We identified a gene that cooperates with MEK inhibitors to forcefully treat PIK3CA mutant colon cancer cells. -catenin, a key molecule of the WNT pathway, emerged as a candidate by protein/Ab Chip array. MEK inhibitor treatment led to a decrease in -catenin in PIK3CA wild-type colon cancer cells but not in PIK3CA mutant colon cancer cells. Tumor regression was promoted by a combination of MEK inhibitor and NVP-TNS656, which targets the WNT pathway. Furthermore, combined inhibition of MEK and -catenin by NVP-TNS656 promoted tumor regression in colon cancer patient-derived xenograft (PDX) models expressing mutant PIK3CA. Taken together, we propose that inhibition of the WNT pathway, particularly -catenin, may bypass resistance to MEK inhibitor in human PIK3CA mutant colon cancer. Additionally, -catenin is a potential PD marker of MEK inhibitor resistance.
Project description:We analyzed publicly available mucosal gene expression data from Crohn's disease (CD) patients pre- and post-infliximab therapy and found that a series of gene expression signature that remains abnormal even if patients achieve clinical remission. Using CMap approach to discover novel therapeutic target for untreatable mechanism of anti-TNFa mAb therapy, we have identified MEK inhibitor exhibiting negatively-correlated effects on reference signature match infliximab therapy untreatable signature. Our findings provide the rationale for testing MEK inhibitor to identify a novel mechanism of action for CD. Gene expression profile was performed to analyze the gene modulation induced by a highly selective MEK inhibitor, and to evaluate whether it normalized reference residual CD signature in vitro.
Project description:Transcripts upregulated or downregulated by HOXB7-MEK signaling were identified for use on the microarray using the Affymetrix GeneChip WT PLUS Reagent Kit in comparison with HOXB7-knockdown S2-013 cells that were transfected with rescue-HOXB7 plasmid and treated with MEK inhibitor, and HOXB7-knockdown S2-013 cells that were transfected with rescue-HOXB7 plasmid but not treated with MEK inhibitor.