Effect of SHP2 Inhibition on mRNA Expression Profiles of GIST Cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE282434 | GEO | 2024/11/30
REPOSITORIES: GEO
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Project description:Purpose: Management of gastrointestinal stromal tumor (GIST) has been revolutionized by the identification of activating mutations in KIT and PDGFRA and the clinical application of receptor tyrosine kinase (RTK) inhibitors in the advanced disease setting. Stratification of GIST into molecularly defined subsets provides insight into clinical behavior and response to approved targeted therapies. Although these RTK inhibitors are effective in the majority of GIST, resistance to these agents remains a significant clinical obstacle. Development of effective treatment strategies for refractory GIST requires identification of novel targets to provide additional therapeutic options. Global kinome profiling has the potential to identify critical signaling networks and reveal protein kinases that are essential in GIST. Experimental Design: Using Multiplexed Inhibitor Beads and Mass Spectrometry paired with a super-SILAC kinome standard, we explored the majority of the kinome in GIST specimens from three GIST subtypes (KIT-mutant, PDGFRA-mutant and succinate dehydrogenase-deficient GIST) to identify novel kinase targets. In vitro and in vivo studies were performed to evaluate the utility of targeting the identified kinases in GIST. Results: Kinome profiling revealed distinct signatures in three GIST subtypes. PDGFRA-mutant GIST had elevated tumor associated macrophage (TAM) kinases and immunohistochemical analysis confirmed increased TAMs present in these tumors. Kinome profiling with loss-of-function assays revealed a significant role for G2-M tyrosine kinase, Wee1, in GIST survival. In vitro and in vivo studies revealed significant efficacy of MK-1775 (Wee1 inhibitor) in combination with avapritinib in both KIT and PDGFRA-mutant GIST cell lines, as well as notable efficacy of MK-1775 as a single agent in the PDGFRA-mutant line. Conclusions: These studies provide strong preclinical justification for the use of MK-1775 in GIST.
2021-09-09 | PXD020720 | Pride
Project description:Activating mutations in either KIT or PDGFRA are present in approximately 90% of gastrointestinal stromal tumors (GISTs). Although treatment with the KIT and PDGFR inhibitor imatinib can control advanced disease in about 80% of GIST patients, the beneficial effect is not durable. Here, we report that ligands from the FGF family reduced the effectiveness of imatinib in GIST cells, and FGF2 and FGFR1 are highly expressed in all primary GIST samples examined. The combination of KIT and FGFR inhibition showed increased growth inhibition in imatinib-sensitive GIST cell lines in the presence or absence of added FGF2 in vitro, and delayed tumor regrowth in vivo. In addition, inhibition of mitogen-activated protein kinase (MAPK) signaling by imatinib was not sustained in GIST cells. An extracellular signal-regulated kinase (ERK) rebound occurred through activation of FGF signaling, and was repressed by FGFR1 inhibition. Downregultation of Sprouty proteins played a role in the imatinib-induced feedback activation of FGF signaling in GIST cells. We used micorarrays to quantify the gene expression levels in GIST cell lines.
2015-01-08 | GSE64762 | GEO
Project description:The protein tyrosine phosphatase SHP2 is crucial for oncogenic transformation of acute myeloid leukemia (AML) cells expressing mutated receptor tyrosine kinases (RTKs), as it is required for full RAS-ERK activation to promote cell proliferation and survival programs. SHP2 allosteric inhibitors act by stabilizing SHP2 in its auto-inhibited conformation and they are currently being tested in clinical trials for tumors with over-activation of the RAS/ERK pathway, alone and in various drug combinations. Using in vitro models, we established acquired resistant cell lines to the allosteric SHP2 inhibitor SHP099 from two FLT3-ITD-positive AML cell lines. We performed both label-free and isobaric labeling quantitative mass spectrometry-based phosphoproteomics to reveal that AML cells can restore phosphorylated ERK (pERK) in presence of SHP099, thus developing adaptive resistance. Mechanistically, SHP2 inhibition induces the tyrosine phosphorylation and feedback-activation of the FLT3 receptor, which in turn phosphorylates SHP2 on Tyrosine 62. This phosphorylation stabilizes SHP2 in its open conformation, preventing SHP099 binding, thus resulting in resistance. Combinatorial inhibition of SHP2 and MEK or SHP2 and FLT3 prevents pERK rebound and resistant cell growth. We observed the same mechanism in a FLT3-mutated B-ALL cell line and in the inv(16)/KITD816Y AML mouse model. Finally, we show that allosteric SHP2 inhibition does not impair the clonogenic ability of normal bone marrow progenitors, supporting its future use for clinical applications.
2023-03-10 | PXD030338 | Pride
Project description:Activating mutations in either KIT or PDGFRA are present in approximately 90% of gastrointestinal stromal tumors (GISTs). Although treatment with the KIT and PDGFR inhibitor imatinib can control advanced disease in about 80% of GIST patients, the beneficial effect is not durable. Here, we report that ligands from the FGF family reduced the effectiveness of imatinib in GIST cells, and FGF2 and FGFR1 are highly expressed in all primary GIST samples examined. The combination of KIT and FGFR inhibition showed increased growth inhibition in imatinib-sensitive GIST cell lines in the presence or absence of added FGF2 in vitro, and delayed tumor regrowth in vivo. In addition, inhibition of mitogen-activated protein kinase (MAPK) signaling by imatinib was not sustained in GIST cells. An extracellular signal-regulated kinase (ERK) rebound occurred through activation of FGF signaling, and was repressed by FGFR1 inhibition. Downregultation of Sprouty proteins played a role in the imatinib-induced feedback activation of FGF signaling in GIST cells. We used micorarrays to quantify the gene expression levels in GIST cell lines. Four GIST cell lines were split and cultured overnight. Cells were harvested for RNA extraction and hybridization on Affymetrix U133plus2 microarrays.
2015-01-08 | E-GEOD-64762 | biostudies-arrayexpress
Project description:GIST is considered to invariably arise through gain-of-function KIT or PDGFRA mutation of the interstitial cells of Cajal (ICC). However, the genetic basis of the malignant progression of GIST is poorly understood. We analysed the expression levels of 54,613 probe sets in 32 surgical samples of untreated GIST of the stomach and small intestine with GeneChip Human Genome U133 Plus 2.0 arrays. Keywords: gene expression array-based, count
2008-06-15 | GSE8167 | GEO
Project description:In contrast to the paucity of clinic GIST (Gastrointestinal stromal tumor; 0.0014 % happening rate), there is a more than twenty thousand times higher rate for miniGISTs, about ~30% of human population could be identified to have miniGISTs. Exploring the molecular differences between miniGISTs and overt GISTs will help us to understand the transformation mechanisms along with GIST progression, but C-kit and PDGFRA mutations analysis failed to identify the differences between these two groups. Conclusion: miniGISTs have significant distinct gene expression profile with overt GISTs by both unsupervised and supervised analysis. Our finding indicated that c-kit and DOG1 expression are the very early events in the genesis of miniGIST and overt GIST, and miniGIST is a molecular distinct group with overt GIST.
2014-12-25 | GSE52666 | GEO
Project description:In addition to KIT and PDGFRA mutations, sequential accumulation of other genetic events is involved in the development and progression of gastrointestinal stromal tumors (GISTs). Until recently, the significance of these other alterations has not been thoroughly investigated. The combination of gene expression profiling and high-resolution genomic copy number analysis offers a detailed molecular portrait of GISTs, providing an essential comprehensive knowledge necessary to guide the discovery of novel target genes involved in tumor development and progression. Fresh tissue specimens from 25 patients with GIST were collected and high-resolution genomic copy number analyses were performed using Affymetrix SNP array 6.0. GIST tumor samples from mutated (KIT or PDGFRA) or Wild Type patients were labeled for hybridization on Affymetrix microarrays. Copy number analysis of Affymetrix SNP6.0 arrays was performed for 25 GIST samples, then compared to gene expression data.
2010-08-27 | E-GEOD-20709 | biostudies-arrayexpress
Project description:A growing body of literature has consolidated the important role of miRNA in a variety of biological processes, in cancer development, acting both as oncogenes and tumor suppressor genes, and in their ability to distinguish tumors according to their diagnostic and prognostic properties.To date, little is known, however, about differences in miRNA expression between KIT/PDGFRA mutant and KIT/PDGFRA WT GIST.
2016-10-03 | E-MTAB-4490 | biostudies-arrayexpress
Project description:Effect of SHP2 Inhibition on mRNA Expression Profiles of GIST Cells
| PRJNA1188572 | ENA