Project description:To investigate the mechanism of BCAT1 in mediating resistance to third-generation EGFR-TKI, we employed RNA-seq analysis to compare the transcriptome signature of ASK120067-resistant NSCLC cells with or without BCAT1 knockdown. Here, gene set enrichment (GSEA) revealed a significant decrease in the expression of genes in glycolysis pathway following small interfering RNA (siRNA)-mediated BCAT1 knockdown, which indicated the role for BCAT1 in supporting TKI resistance through upregulation of glycolysis.
Project description:In this report, we revealed that branched chain amino acid transaminase 1 (BCAT1) is highly enriched in both mouse and human TKI-resistant CML cells. Leukemia was almost completely abrogated upon BCAT1 knockdown during transplantation in a BCR-ABLT315I-induced murine TKI-resistant CML model . Moreover, knockdown of BCAT1 led to a dramatic decrease in the proliferation of TKI-resistant human leukemia cell lines. BCAA/BCAT1 signaling enhanced the phosphorylation of CREB, which is required for maintenance of TKI-resistant CML cells. Importantly, blockade of BCAA/BCAT1 signaling efficiently inhibited leukemogenesis both in vivo and in vitro.
Project description:Epidermal growth factor receptor (EGFR) mutations are leading oncogenic drivers in non-small cell lung cancer (NSCLC). Many third-generation EGFR tyrosine kinase inhibitors (TKIs) have been developed to target EGFR T790M and activating mutations. Osimertinib (AZD9291) was the first approved drug and is now the standard-of-care therapy for untreated EGFR-mutated NSCLC. Our team previously identified ASK120067, for which we have submitted a new drug application (NDA) in China. Although third-generation EGFR TKIs exhibit favorable antitumor effects in NSCLC treatment, acquired resistance with largely unexplored mechanisms still limits their long-term efficacy. In this study, we aimed to investigate the molecular mechanisms underlying resistance to EGFR TKIs and identify new therapeutic strategies for the treatment of NSCLC. Methods: Elevated expression of BCAT1 in EGFR TKI-resistant lung cancer cells was identified using stable isotope labeling by amino acids in cell culture (SILAC)-based proteomics analysis and verified with Western blotting and RT‒qPCR.
Project description:This SuperSeries is composed of the following subset Series: GSE29711: Molecular Mechanisms of Bortezomib Resistant Adenocarcinoma cells [CGH data] GSE29712: Molecular Mechanisms of Bortezomib Resistant Adenocarcinoma cells [GEP data] Refer to individual Series
Project description:Previously, we have identified cytosolic form of the branched chain amino-acid transaminase 1 (BCAT1) as notably hypomethylated in low-malignant potential (LMP) and high-grade (HG) serous epithelial ovarian tumors, compared to normal ovarian tissues. Here we show that BCAT1 is strongly overexpressed in both LMP and HG serous EOC tumors, thus suggesting that epigenetic mechanisms might be implicated in BCAT1 overexpression in serous epithelial ovarian cancer (EOC). Knockdown of the BCAT1 expression in EOC cells led to sharp decrease of cell proliferation and induced S-phase cell cycle arrest. Additionally, BCAT1 suppression significantly inhibited EOC cell migration and invasion. Gene expression profiling and consecutive network and pathway analyses confirmed these findings, as numerous genes and pathways known previously to be implicated in ovarian tumorigenesis, including EOC tumor invasion and metastasis, were found to be downregulated upon BCAT1 suppression, while some tumor suppressor genes were induced. Taken together, our data are indicative for a strong oncogenic potential of the BCAT1 gene in advanced EOC and identify this transaminase as a novel EOC biomarker and putative EOC therapeutic target.