Dysregulated genes associated with acquired resistance
ABSTRACT: This study was conducted to identify dysregulated genes associated with acquired resistance to chemotherapy. Endoscopic biopsy samples were collected from CF-treated metastatic gastric cancer patients prior to therapy and following the development of resistance to therapy.
Project description:This study was conducted to identify transcriptional profiles predictive of a clinical response of metastatic gastric cancer patients to cisplatin and fluorouracil (CF) combination chemotherapy. Endoscopic biopsy samples were collected from CF-treated metastatic gastric cancer patients prior to therapy and following the development of resistance to therapy.
Project description:This SuperSeries is composed of the following subset Series: GSE14208: Clinical response of metastatic gastric cancer patients to cisplatin and fluorouracil (CF) combination chemotherapy GSE14209: Dysregulated genes associated with acquired resistance Refer to individual Series
Project description:This study was conducted to identify dysregulated genes associated with acquired resistance to chemotherapy. Overall design: Endoscopic biopsy samples were collected from CF-treated metastatic gastric cancer patients prior to therapy and following the development of resistance to therapy.
Project description:This study was conducted to identify transcriptional profiles predictive of a clinical response of metastatic gastric cancer patients to cisplatin and fluorouracil (CF) combination chemotherapy. Overall design: Endoscopic biopsy samples were collected from CF-treated metastatic gastric cancer patients prior to therapy and following the development of resistance to therapy.
Project description:Chronic Pseudomonas aeruginosa infections evades antibiotic therapy and are associated with mortality in cystic fibrosis (CF) patients. We find that in vitro resistance evolution of P.aeruginosa towards clinically relevant antibiotics leads to phenotypic convergence towards distinct states. These states are associated with collateral sensitivity towards several antibiotic classes and encoded by mutations in antibiotic resistance genes, including transcriptional regulator nfxB. Longitudinal analysis of isolates from CF patients reveals similar and defined phenotypic states, which are associated with extinction of specific sub-lineages in patients. In depth investigation of chronic P.aeruginosa populations in a CF patient during antibiotic therapy revealed dramatic genotypic and phenotypic convergence. Notably, fluoroquinolone-resistant subpopulations harboring nfxB mutations were eradicated by antibiotic therapy as predicted by our in vitro data. This study supports the hypothesis that antibiotic treatment of chronic infections can be optimized by targeting phenotypic states associated with specific mutations to improve treatment success in chronic infections.
Project description:Acquired drug resistance and tumour relapse impacts the majority of patients being treated with tyrosine kinase inhibitors (TKIs) and remains a key challenge in modern anti-cancer therapy. The lack of clinically effective therapeutic strategies to overcome drug resistance represents a significant unmet need. Understanding the signalling pathways that drive drug resistance will facilitate the development of new salvage therapies to effectively treat patients with secondary TKI resistance. In this study, we utilise quantitative mass spectrometry to characterise the global phosphoproteomic alterations that accompany the acquisition of resistance to two FDA-approved multi-target TKIs, pazopanib and dasatinib, in the A204 rhabdoid tumour cell line. Our analysis finds that only a limited fraction of the quantified phosphoproteome (<10%) is altered upon the acquisition of drug resistance with pazopanib resistant cells displaying elevated phosphorylation levels in cytoskeletal regulatory pathways and dasatinib resistant cells showing an upregulation of components of the insulin receptor/IGF1-R signalling pathway. Drug response profiling with a targeted panel of small molecule inhibitors rediscovers several previously reported vulnerabilities associated with pazopanib and dasatinib resistance and identifies a new dependency to the second generation HSP90 inhibitor NVP-AUY-922. This study provides a useful resource detailing the candidate signalling determinants of acquired TKI resistance; and reveals a therapeutic approach of inhibiting HSP90 function as a means of salvage therapy to overcome pazopanib and dasatinib resistance.
Project description:Female BRCA1 mutation carriers have a nearly 80% probability of developing breast cancer during their life-time. We hypothesized that the breast epithelium at risk in BRCA1 mutation carriers harbors mammary epithelial cells (MECs) with altered proliferation and differentiation properties. Microarray studies revealed that PMEC colonies from BRCA1 mutation carriers anticipate expression profiles found in BRCA1-related tumors, and that the EGFR pathway is upregulated in BRCA1 mutation carriers compared ton non BRCA1 mutation carriers. Keywords: Class comparison and pathway analysis 10 colonies were collected and RNA was isolated using the Absolutely RNA Nanoprep kit, Stratagene. The arrays included duplicates from four normal controls and from two BRCA1 mutation carriers and single arrays from another two BRCA1 mutation carriers.
Project description:Crohn's Disease (CD) is a chronic inflammatory disease of the intestinal tract. We performed a whole-genome transcriptional analysis using colonic biopsies from CD patients before and after anti-TNF-α therapy. Involved colonic samples from Crohn's disease patients and healthy colonic samples from non-inflammatory controls were collected for RNA extraction and hybridization on Affymetrix microarrays. Inclusion criteria for CD patients were: age between 18 and 70, diagnosis of CD established at least 4 months before inclusion and exclusion of concomitant infection. Active disease was defined by endoscopic and clinical score: endoscopic active disease was defined as a CD endoscopic index of severity (CDEIS) of 5 or more and the presence of large ulcers (> 0.5 cm diameter) in at least one of the explored segments. Clinical activity was defined as a CD activity index (CDAI) above 150. Finally, a total of 39 biopsies were analyzed: 17 healthy controls, 10 active CD without anti-TNF therapy, 5 active CD with anti-TNF therapy (non-responders) and 7 inactive CD with anti-TNF therapy (responders).
Project description:Anti-EGFR antibodies are effective in therapies for late-stage colorectal cancer (CRC); however, many tumours are unresponsive or develop resistance. We performed genomic analysis of intrinsic and acquired resistance to anti-EGFR therapy in prospectively collected tumour samples from 25 CRC patients receiving cetuximab (an EGFR inhibitor). Of 25 CRC patients, 13 displayed intrinsic resistance to cetuximab; 12 were intrinsically sensitive. We obtained six re-biopsy samples at acquired resistance from the intrinsically sensitive patients. NCOA4–RET and LMNA–NTRK1 fusions and NRG1 and GNAS amplifications were found in intrinsic-resistant patients. In cetuximab-sensitive patients, we found KRAS K117N and A146T mutations in addition to BRAF V600E, AKT1 E17K, PIK3CA E542K, and FGFR1 or ERBB2 amplifications. The comparison between baseline and acquired-resistant tumours revealed an extreme shift in variant allele frequency of somatic variants, suggesting that cetuximab exposure dramatically selected for rare resistant subclones that were initially undetectable. There was also an increase in epithelial-to-mesenchymal transition at acquired resistance, with a reduction in the immune infiltrate. Furthermore, characterization of an acquired-resistant, patient-derived cell line showed that PI3K/mTOR inhibition could rescue cetuximab resistance. Thus, we uncovered novel genomic alterations that elucidate the mechanisms of sensitivity and resistance to anti-EGFR therapy in metastatic CRC patients.
Project description:Patients who cleared HCV viremia early during therapy tended to show favorable outcomes, whereas patients who needed a longer period to clear HCV had poorer outcomes. We explored the mechanisms of treatment resistance by comparing hepatic gene expression before and during treatment We explored the mechanisms of treatment resistance by comparing hepatic gene expression before and during treatment. Liver biopsy was performed in 30 patients before and one week after starting combination therapy with IFN + Rib. Hepatocytes and liver-infiltrating lymphocytes (LILs) were obtained from 12 patients using laser capture micro dissection (LCM).