Project description:Spatial transcriptome profile was assessed from patients' tumor tissues to receive Osimertinib. We uncovered the mechanism of EGFR-TKI resistance, and tumor progression to develop thepeutic strategy.
Project description:Whole exome sequencing was performed on set of 48 DNA samples obtained from 16 EGFR mutated NSCLC patients whose tumors progressed following EGFR-TKI treatment. The DNA samples included baseline biopsy, rebiopsy and blood from the same patient. By comparing the variants in rebiopsy tumors and baseline tumors we aim to understand the genomic alterations responsible for the development of EGFR-TKI resistance in NSCLC patients.
Project description:Intratumoral heterogeneity in EGFR mutant NSCLC results in divergent resistance mechanisms in response to EGFR tyrosine kinase inhibition We used microarrays to investigate the gene expression underlying EGFR TKI resistance with a mesenchymal phenotype.
Project description:Metabolic reprogramming is widely known as a hallmark of cancer cells to allow adaptation of cells to sustain survival signals. In the past decade, altered lipid metabolism has been recognized to be a property of malignant cells. In this report, we describe a novel oncogenic signaling pathway exclusively in tyrosine kinase inhibitor (TKI)-resistant epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC). EGFR mediates TKI-resistance through regulation of the fatty acid synthase (FASN), and inhibition of this pathway using the FASN inhibitor Orlistat, triggers cell death and reduces tumor sizes both in culture systems and in vivo. Together, data shown here provide compelling evidence that the fatty acid metabolism pathway is a candidate target for TKI-resistant NSCLC treatment.
Project description:Epidermal growth factor receptor (EGFR) harboring active mutations, Del19 and L858R, are most common oncogenic mutations in in non-small cell lung cancer (NSCLC) patients. The preferred treatment at first line is tyrosine kinase inhibitor (TKI) administration while the TKI-resistance usually develops because of acquiring the secondary EGFR T790M mutant. Protein-protein interactions (PPIs) constitute the signaling scaffold and thus aberrant PPIs ascribed to mutations often results in dysregulations of downstream signaling cascades. Affinity purification coupled mass spectrometry (AP-MS) was utilized to characterize the EGFR PPIs in four NSCLC cells which carry different EGFR subtypes representing as TKI-sensitive and -resistant models in this study. The EGFR interactomes of TKI-resistant NSCLC cells presented higher diversity of subcellular distribution as well as the hyperactive EGFR trafficking. Furthermore, gefitinib perturbation activated autophagy-mediated EGFR degradation in TKI-resistant NSCLC models and inhibiting autophagy process indeed reduced the TKI-resistance against gefitinib as cytotoxicity was significantly improved. Alternatively, gefitinib induced EGFR translocation toward cell periphery through Rab7 ubiquitination in TKI-sensitive models which may confer TKIs more chance to suppress EGFR activity. In brief, acquired T790M EGFR mutation rewired the EGFR inherent interactomes and thus guided EGFR moving toward distinct trafficking routes, EGFR recycling or autophagy-mediated degradation, in response to TKI insult in TKI-sensitive and -resistant NSCLC cells. These finding suggest that manipulation or combined autophagy inhibition may provide us a novel therapeutic strategy to manage TKI-resistance and tumor relapse in NSCLC.
Project description:Lung adenocarcinoma cells harboring epidermal growth factor receptor (EGFR) mutations are sensitive to EGFR tyrosine kinase inhibitors (TKIs). Prolonged cancer treatment will induce the development of acquired resistance to EGFR TKI. To gain insight into the molecular mechanisms of EGFR-TKIs resistance, we generate EGFR-TKI-resistant HCC827-8-1 cells to be analyzed by microarray with their parental HCC827cells. gefitinib resistant HCC827-8-1 cells with three replications; gefitinib-sensitive HCC827 cells with three replications
Project description:Patients with EGFR mutations exhibit immunosuppressive microenvironments, limiting responsiveness to immunotherapy. In our analysis, 25 Korean patients diagnosed with NSCLC harboring common EGFR mutations (L858R and exon 19 microdeletion) that received EGFR-TKI treatment was compared before and after treatment. 25 patients were analyzed overall, and 14 patients were analyzed in the paired analysis who received first-line osimertinib. Among 171 ROIs, 68ROIs were used for tumor paired analysis, and 51 ROIs for immune region.