Whole-genome shRNA to identify sensitizers to MEK and IGF1R inhibitors
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE118685 | GEO | 2021/08/15
REPOSITORIES: GEO
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Project description:Whole-genome shRNA to identify sensitizers to MEK and IGF1R inhibitors
| PRJNA486452 | ENA
Project description:The clinical efficacy of EGFR kinase inhibitors gefitinib and erlotinib is limited by the development of drug resistance. The most common mechanism of drug resistance is the secondary EGFR T790M mutation. Strategies to overcome EGFR T790M mediated drug resistance include the use of mutant selective EGFR inhibitors, including WZ4002, or by the use of high concentrations of irreversible quinazoline EGFR inhibitors such as PF299804. In the current study we develop drug resistant versions of the EGFR mutant PC9 cell line which reproducibly develops EGFR T790M as a mechanism of drug resistance to gefitinib. Neither PF299804 resistant (PFR) or WZ4002 resistant (WZR) clones of PC9 harbor EGFR T790M. Instead, they demonstrate activated IGF1R signaling as a result of loss of expression of IGFBP3 and the IGF1R inhibitor, BMS 536924, restores EGFR inhibitor sensitivity. Intriguingly, prolonged exposure to either PF299804 or WZ4002 results in the emergence of a more drug resistant subclone which contains ERK activation. A MEK inhibitor, CI-1040, partially restores sensitivity to EGFR/IGF1R inhibitor combination. Moreover, an IGF1R or MEK inhibitor used in combination with either PF299804 or WZ4002 completely prevents the emergence of drug resistant clones in this model system. Our studies suggest that more effective means of inhibiting EGFR T790M will prevent the emergence of this common drug resistance mechanism in EGFR mutant NSCLC. However, multiple drug resistance mechanisms can still emerge. Preventing the emergence of drug resistance, by targeting pathways activated in resistant cancers before they emerge, may be a more effective clinical strategy. Total of three samples with duplicate or triplicate each were analyzed.
2012-10-01 | E-GEOD-38404 | biostudies-arrayexpress
Project description:The clinical efficacy of EGFR kinase inhibitors gefitinib and erlotinib is limited by the development of drug resistance. The most common mechanism of drug resistance is the secondary EGFR T790M mutation. Strategies to overcome EGFR T790M mediated drug resistance include the use of mutant selective EGFR inhibitors, including WZ4002, or by the use of high concentrations of irreversible quinazoline EGFR inhibitors such as PF299804. In the current study we develop drug resistant versions of the EGFR mutant PC9 cell line which reproducibly develops EGFR T790M as a mechanism of drug resistance to gefitinib. Neither PF299804 resistant (PFR) or WZ4002 resistant (WZR) clones of PC9 harbor EGFR T790M. Instead, they demonstrate activated IGF1R signaling as a result of loss of expression of IGFBP3 and the IGF1R inhibitor, BMS 536924, restores EGFR inhibitor sensitivity. Intriguingly, prolonged exposure to either PF299804 or WZ4002 results in the emergence of a more drug resistant subclone which contains ERK activation. A MEK inhibitor, CI-1040, partially restores sensitivity to EGFR/IGF1R inhibitor combination. Moreover, an IGF1R or MEK inhibitor used in combination with either PF299804 or WZ4002 completely prevents the emergence of drug resistant clones in this model system. Our studies suggest that more effective means of inhibiting EGFR T790M will prevent the emergence of this common drug resistance mechanism in EGFR mutant NSCLC. However, multiple drug resistance mechanisms can still emerge. Preventing the emergence of drug resistance, by targeting pathways activated in resistant cancers before they emerge, may be a more effective clinical strategy.
2012-10-01 | GSE38404 | GEO
Project description:IGF1 and IGF1 receptors (IGF1R) are present in the adult heart and have been shown to be essential for myocardial performance. Insulin-like growth factor 1 (IGF1) is produced in numerous tissues particularly by the liver in response to growth hormone stimulation and is an important factor in the regulation of post-natal growth and development. We have generated and characterized transgenic mice over-expressing the IGF1R. We crossed IGF1R transgenic mice with dominant negative (dn)PI3K (p110) and with constitutively active (ca)PI3K(p110) transgenic mice. Expression profiling was performed on the ventricles of IGF1R, IGF1R-caPI3K, IGF1R-dnPI3K, caPI3K, dnPI3K transgenic female mice at 3 months of age. Non-transgenic littermates were used as controls.
2007-09-29 | E-GEOD-1143 | biostudies-arrayexpress
Project description:Purpose:Renal injury with the loss of podocyte was characteristic pathology of diabetic nephropathy (DN) and correlated with increased albuminuria. Many studies have found the nephroprotective effect of the novel inhibitors of sodium-glucose cotransporter 2 (SGLT2-is), like Dapagliflozin, delaying the progression of DN. However, the underlying mechanisms of SGLT2 associated with podocyte injury are still not fully elucidated. Methods: Through mRNA sequencing, streptozotocin-induced and Dapagliflozin-intraperitoneal injection mice models were established to explore potential mechanism between Dapagliflozin and renal phenotype. And all changes referring this observed pathway were proven repeatedly in podocyte. Results: Here, we generated the streptozotocin-induced DN models and found the accumulation of nephrotoxin and pathological lesions of the kidney, including interstitial inflammatory infiltration, mesangial expansion and glomerular sclerosis, while low expression of SGLT2 mitigated these injuries in Dapagliflozin-treated mice. Moreover, mRNA expression profile in these treated models determined the significance of insulin-like growth factor-1 receptor (IGF1R)/PI3K regulatory axis in glomerular injury. Particularly, SGLT2-is inhibited the increase of mesenchymal marker, α-SMA and the decrease of podocyte marker, nephrin at the gene or protein level. KEGG analysis also showed the enrichment of phosphatidylinositol signaling system and TGF-β/smad pathway. In parallel, the protein level of IGF1R, phosphorylated PI3K, and α-SMA were increased in high-glucose stimulated human podocyte, and reduced in Dapagliflozin (50nM and 100nM) or OSI-906 (inhibitor of IGF1R, 60nM) used groups. Notably, combination of the two inhibitors produced an accumulative effect in the protection of podocyte integrity. Mechanistically, IGF1 or IGF2 could bind to IGF1 receptors to mediate the epithelial-mesenchymal transition (EMT) of diabetic podocyte in response to the upregulation of SGLT2. Indeed, we enrolled the urine and plasma samples from a cohort consisting of 13 healthy people, and a cohort of 19 patients with DN using SGLT2-inhibitors (n=9) or not (n=10). Compared with pure DN patients, Elisa results suggested an increased circulation and excretion level of IGF1/2 in SGLT2-is used DN cohort. Conclusions: Taken together, our study reported the key role of SGLT2/IGF1R/PI3K signaling in regulating podocyte EMT. Modulating the IGF1R expression may provide a novel idea for DN therapy.
2022-10-19 | GSE200322 | GEO
Project description:Tankyrases (TNKS) play roles in Wnt signaling, telomere homeostasis and mitosis, offering attractive targets for anti-cancer treatment. Using unbiased combination screening in a large panel of cancer cell lines, we have identified a strong synergy between TNKS and MEK inhibitors in KRAS mutant cancer cells. Our study uncovers a novel function of TNKS in the relief of a feedback loop induced by MEK inhibition on FGFR2 signaling pathway. Moreover, dual inhibition of TNKS and MEK leads to more robust apoptosis and anti-tumor activity both in vitro and in vivo than effects observed by previously reported MEK inhibitor combinations. Altogether, our results show how a novel combination of TNKS and MEK inhibitors can be highly effective in targeting KRAS mutant cancers by suppressing a newly discovered resistance mechanism. This experiment is designed to detect genes differentially expressed in the combination treatment compared to others SW480 cells were seeded in 10cm dishes and treated for 4h and 16h with DMSO, TNKS inhibitor (TNKSi : NVP-TNKS656), MEK inhibitor (MEKi : AZD6244) or the combination of both at 1uM final
2014-03-06 | E-GEOD-55624 | biostudies-arrayexpress
Project description:Purpose: The clinical use of MEK inhibitors in uveal melanoma is limited by the rapid acquisition of resistance. The current study has used multi-omics approaches and drug screens to identify the pan-HDAC inhibitor panobinostat as an effective strategy to limit MEK inhibitor resistance. Experimental Design: Mass spectrometry-based proteomics and RNA-Seq was used to identify the signaling pathways involved in the escape of uveal melanoma cells from MEK inhibitor therapy. Mechanistic studies were performed to evaluate the escape pathways identified and the efficacy of the MEK-HDAC inhibitor combination was demonstrated in multiple in vivo xenograft models of uveal melanoma. Results: We identified a number of putative escape pathways that were upregulated following MEK inhibition including the PI3K/AKT pathway, ROR1/2 and IGF1R signaling. MEK inhibition was also associated with a widespread increase in GPCR expression, particularly the Endothelin B receptor and that this contributed to therapeutic escape through YAP signaling. A screen of 289 clinical grade compounds identified HDAC inhibitors as potential candidates that suppressed the adaptive YAP and AKT signaling that followed MEK inhibition. In vivo xenograft studies revealed the MEK-HDAC inhibitor combination to outperform either agent alone, leading to a long-term decrease of tumor growth and the suppression of adaptive PI3K/AKT and YAP signaling. Conclusions Together our studies have identified GPCR-mediated YAP activation and RTK-driven AKT signaling as key pathways involved in the escape of uveal melanoma cells from MEK inhibition. We further demonstrate that HDAC inhibition is a promising combination partner for MEK inhibitors in uveal melanoma.
2020-05-26 | PXD013988 | Pride
Project description:Aberrant RAS/MAPK signaling, a common driver of oncogenesis, can be therapeutically targeted with clinically approved MEK inhibitors. Single agent therapy ultimately results in tumor outgrowth in most settings and combination therapies are required to achieve significant clinical benefit in most advanced cancers. Here we focus on identifying MEK inhibitor-based combination therapies in RAS-mutant neuroblastoma. Mutations that activate the RAS/MAPK signaling pathway, while rare at diagnosis, are more frequent in relapsed neuroblastoma. More than 50% of children with high-risk neuroblastoma ultimately relapse and treatment options for relapsed neuroblastoma are limited so most children with relapsed disease do not survive. Here we use a genome-scale CRISPR-Cas9 functional genomic screen to identify genes that, when lost, sensitize RAS-mutant neuroblastoma to MEK inhibition. We discover that loss of either CCNC or CDK8, two members of the mediator kinase module, sensitizes neuroblastoma to MEK inhibition. Furthermore, we demonstrate that small molecule kinase inhibitors of CDK8 improve response to MEK inhibitors in vitro and in vivo in RAS-mutant neuroblastoma and other adult solid tumors, suggesting that the addition of CDK8 inhibitors could improve clinical outcome. Using transcriptional profiling, we unexpectedly find that loss of CDK8 or CCNC antagonizes the transcriptional signature induced by MEK inhibition. When combined, loss of CDK8 or CCNC prevents the compensatory upregulation of pro-growth gene expression induced by MEK inhibition. These findings propose a new therapeutic combination for RAS-mutant neuroblastoma and may have clinical relevance for other RAS-driven malignancies.
2023-02-22 | GSE190178 | GEO
Project description:Tpl-2 and MEK small molecule inhibitors
| PRJNA328166 | ENA
Project description:The use of BRAF and MEK inhibitors for patients with BRAF-mutant melanoma is limited as patients relapse on treatment as quickly as 6 months due to acquired resistance. We generated trametinib and dabrafenib resistant melanoma (TDR) cell lines to the MEK and BRAF inhibitors, respectively. TDR cells exhibited increased viability and maintenance of downstream p-ERK and p-Akt as compared to parental cells. Receptor tyrosine kinase arrays revealed an increase in p-IGF1R and p-IR in the drug resistant cells versus drug sensitive cells. RNA-sequencing analysis identified IGF1R and INSR upregulated in resistant cell lines compared to parental cells. Analysis of TCGA PanCancer Atlas (skin cutaneous melanoma) showed that patients with a BRAF mutation and high levels of IGF1R and INSR had a worse overall survival. BMS-754807, an IGF1R/IR inhibitor, suppressed cell proliferation along with inhibition of intracellular p-Akt in TDR cells. Dual inhibition of IGF1R and INSR using siRNA reduced cell proliferation. The combination of dabrafenib, trametinib, and BMS-754807 treatment reduced in vivo xenograft tumor growth. Examining the role of IGF1R and IR in mediating resistance to BRAF and MEK inhibitors will expand possible treatment options to aid in long-term success for BRAF-mutant melanoma patients.
| S-EPMC8616282 | biostudies-literature