MicroRNA and mRNA regulatory network in ALK-rearranged lung adenocarcinoma
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ABSTRACT:
PROVIDER: PRJNA527104 | ENA |
REPOSITORIES: ENA
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Project description:We examined microarray data of miRNAs and mRNAs from 77 cases of lung adenocarcinoma, including 42 ALK-rearranged cases. a multistep bioinformatics approach to build a miRNA–mRNA regulatory network in ALK-rearranged lung adenocarcinoma.
2022-03-14 | GSE128310 | GEO
Project description:We examined microarray data of miRNAs and mRNAs from 77 cases of lung adenocarcinoma, including 42 ALK-rearranged cases. a multistep bioinformatics approach to build a miRNA–mRNA regulatory network in ALK-rearranged lung adenocarcinoma.
2022-03-14 | GSE128309 | GEO
Project description:MicroRNA and mRNA regulatory network in ALK-rearranged lung adenocarcinoma [miRNA]
| PRJNA527106 | ENA
Project description:MicroRNA and mRNA regulatory network in ALK-rearranged lung adenocarcinoma [mRNA]
| PRJNA527107 | ENA
Project description:Acquired drug resistance is the major therapeutic obstacle to maintenance treatment of advanced-stage non-small cell lung cancer. Lung adenocarcinoma (ADC) harboring driver mutations also showed poor response to immune checkpoint inhibitors (ICIs). Underlying mechanisms of how drug insensitivity evolves remain unclear. Here we explored the intratumoral heterogeneity of tyrosine kinase inhibitor (TKI)-resistant anaplastic lymphoma kinase (ALK)-rearranged lung ADC organoids using single-cell RNA-sequencing (scRNA-seq) transcriptomic analysis. IL-17 signaling pathway was found highly induced in a subpopulation of pre-existing ALK-TKI-resistant cells. These drug-tolerant persister (DTP) cells, also found to have high surface intracellular adhesion molecule 1 (ICAM-1) expression level, were more resistant towards ALK-TKI and expressed a higher level of cancer-stem cell transcriptional factors. Moreover, tumor cells with high ICAM-1 expression were found spatially correlated with RORɣt+ Th17 infiltration in ALK-rearranged NSCLC resected tumor tissues. In conclusion, our data revealed marked intratumoral heterogeneity in ALK-rearranged tumor, and pre-existing DTP cells may contribute to the development of drug insensitivity in ALK-rearranged lung ADC.
2023-08-09 | GSE223779 | GEO
Project description:Spatial evaluation of transcriptomic and proteomic data in ALK rearranged lung cancer - a pilot study
2022-04-20 | MSV000089286 | MassIVE
Project description:DNA microarray analysis of ALK-rearranged lung cancer cells (H3122) comparing control untreated cells with cells treated by YHO-1701 (STAT3 inhibitor) for 24h.
2022-01-21 | GSE193858 | GEO
Project description:The rearrangement of anaplastic lymphoma kinase (ALK) occurs in 3%-5% of patients with non-small cell lung cancer (NSCLC) and confers sensitivity to ALK-tyrosine kinase inhibitors (TKIs). For the treatment of patients with ALK-rearranged NSCLC, various additional ALK-TKIs have been developed. Ceritinib is a second-generation ALK-TKI and has shown great efficacy in the treatment of patients with both newly diagnosed and crizotinib, a first-generation ALK-TKI, refractory ALK-rearranged NSCLC. However, tumors can also develop ceritinib resistance. This may result from secondary ALK mutations, but other mechanisms responsible for this have not been fully elucidated. In this study, we explored the mechanisms of ceritinib resistance by establishing ceritinib-resistant, echinoderm microtubule-associated protein-like 4 (EML4)-ALK-positive H3122 cells and ceritinib-resistant patient-derived cells. We identified a mechanism of ceritinib resistance induced by bypass signals that is mediated by the overexpression and activation of fibroblast growth factor receptor 3 (FGFR3). FGFR3 knockdown by small hairpin RNA or treatment with FGFR inhibitors was found to resensitize the resistant cells to ceritinib in vitro and in vivo. FGFR ligands from either human serum or fetal bovine serum were able to activate FGFR3 and induce ceritinib resistance. A detailed analysis of ceritinib-resistant patient-derived specimens confirmed that tyrosine-protein kinase Met (cMET) amplification induces ceritinib resistance. Amplified cMET counter-activated EGFR and/or Her3, and induced ceritinib resistance. These results reveal multiple ceritinib resistance mechanisms and suggest that ceritinib resistance might be able to overcome by identifying precise resistance mechanisms.
2022-08-14 | GSE77764 | GEO
Project description:Anaplastic lymphoma kinase (ALK) inhibitors, such as alectinib (ALC), have dramatic therapeutic effects on ALK-rearranged lung cancer, but cures are usually not achieved. We focused on tumor cells that survive ALK inhibitor administration and hypothesized that targeted therapy for these cells could provide complete remission. To explore survival factors, we established patient-derived cell lines and screened them using proteome analysis. Three ALK-rearranged ALC-sensitive cell lines (KTOR-1, KTOR-2, KTOR-3) were established from 3 patients; the 50% inhibitory concentrations (IC50)s for ALC were 24-65 nM. Comprehensive protein expression profiles of the 3 cells indicated that exposure to ALC significantly enriched proteins related to actin and extracellular matrix (ECM) adhesion. We focused on Yes-associated protein 1 (YAP1), which is activated by ECM adhesion and actin fiber accumulation. Nuclear localization of YAP1 (an activation marker of YAP1) was assessed using immunohistostaining. In KTOR1-3 and H2228 cells from an ALK-rearranged line purchased from ATCC, exposure to ALC in vitro promoted YAP1 accumulation in the nucleus. BALB/nu mice xenograft models of H2228 or KTOR1 were administered ALC (8 mg/kg/day, N=4) or a vehicle (N=4) for 7 days, and tumors were evaluated. In ALC-administered tumors, YAP1 was localized to the nucleus, which was rarely the case in vehicle-administered tumors. The expression of pro-apoptosis factors Mcl-1 and Bcl-xL also increased after exposure to ALC in vitro, but the increment was cancelled by YAP1 inhibition by siRNA or verteporfin (VER), a non-specific YAP1 inhibitor. Exposure to ALC with combinatorial YAP1 inhibition significantly increased Caspase 3/7 activity. To address the treatment effects of YAP1 inhibition, a YAP1-activated H2228 cell line (H2ARY) was established by exposing H2228 cells to 100-300 nM of ALC for 3 months and thorough subsequent cloning. The H2ARY had lower sensitivity to ALC in vitro than parental H2228 (IC50: 1.4 μM vs 315 nM, 96 h) and restored the sensitivity by YAP1 inhibition (208 nM with VER 1 μM, 312 nM with siYAP1). Twenty-four xenograft models (mean volume: 199 mm3) of H2ARY on BALB/nu mice were randomized (Day 0) into 4 treatment groups to receive ALC monotherapy (8 mg/kg daily, N=6), VER monotherapy (12.5 mg/kg twice a week, N=7), combination (N=7), or vehicle (N=5). On day 15, the tumor volume of the vehicle and VER monotherapy groups reached > 800 mm3, with no significant differences among the groups. On day 33, the tumors of the combination group were significantly smaller than those of the ALC monotherapy group (187 vs 761 mm3, P = 0.0125). Exposure to ALC-activated YAP1 may regulate anti-apoptotic activity by controlling the expression of Mcl-1 and Bcl-xL in ALK-rearranged lung cancer cells. This is the first evidence that combinatorial therapy against ALK and YAP1 could enhance ALK-rearranged tumor treatment.
2019-07-28 | PXD014783 | JPOST Repository
Project description:Single-cell transcriptomic analysis uncovers intratumoral heterogeneity and drug-tolerant persister in ALK-rearranged lung adenocarcinoma
| PRJNA928366 | ENA