Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Reduced mTORC1 activity is associated with responsiveness to MEK inhibition (PD0325901) in gastric cancer cells.

ABSTRACT: Since gastric cancer (GC) is characterized by amplifications of receptor tyrosine kinases (RTK) and KRAS, targeting the RTK/KRAS downstream pathways could contribute to broader applicability of molecular targeted therapy in GC. Here, we assembled a panel of 49 GC cell lines and screened predictors for responsiveness to RAF/MEK/ERK pathway inhibition by comparing their sensitivity to MEK inhibition with alteration status of RTK/KRAS and phosphorylation status of RTK/KRAS downstream molecules. We found that GC cells with MET amplification or KRAS mutation tend to be sensitive to MEK inhibition. Furthermore, lower phosphorylation levels of mTORC1 targets, p70S6K and 4EBP1, was also significantly associated with sensitivity to MEK inhibition. Interestingly, the sensitive cells showed reduced mTORC1 activity accompanied by decreased rate of protein synthesis after MEK inhibition, suggesting that antiproliferative effect of MEK inhibition may be exerted through inhibition of protein synthesis, which was caused by reduced mTORC1 activity. Mechanistically, expression of some mTORC1 negative regulators, such as DDIT4, FOXO3, SESN1 and TSC1, were induced by MEK inhibition in highly-sensitive cell lines and knockdown of these negative regulators partially alleviated the suppression of mTORC1 activity and antiproliferative effect of MEK inhibition. Our data suggest that a subset of GCs, which would be distinguishable according to the predictive markers we identified, may be sensitive to MEK inhibition and have implications for the strategy in clinical trial of MEK inhibitors for GC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE74842 | GEO | 2016/12/31

SECONDARY ACCESSION(S): PRJNA301631

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Transcription profiling of human cell lines in culture (n=12) and murine xenografts (n=2) were treated with the MEK inhibitor PD0325901 or vehicle alone as controlPaired MEK inhibited and control

Project description:This study used microarray expression analysis to identify global changes in transcript alteration in response to MEK inhibition. Genes under ERK control were identified in a panel of V600E BRAF and RTK-activated tumor cells and xenografts, using short-term inhibition of ERK activity using the MEK inhibitor PD0325901 (Pfizer). Experiment Overall Design: Cell lines growing in culture (n=12) and murine xenografts (n=2) were treated with the MEK inhibitor PD0325901 or vehicle alone as control. Paired analysis of MEK inhibited to control samples was performed for two groups of tumor cells, V600E BRAF and RTK.

2009-02-21 | E-GEOD-10087 | biostudies-arrayexpress

Defining key signaling nodes and therapeutic biomarkers in NF1-mutant cancers

Project description:The NF1 tumor suppressor encodes a RAS GTPase-Activating Protein (RasGAP). Accordingly, deregulated RAS signaling underlies the pathogenesis of NF1-mutant cancers. However, while various RAS effector pathways have been shown to function in these tumors, it is currently unclear which specific proteins within these broad signaling pathways represent optimal therapeutic targets. Here we identify mTORC1 as the key PI3K pathway component in NF1-mutant nervous system malignancies and conversely show that mTORC2 and AKT are dispensable. We also report that combined mTORC1/MEK inhibition is required to promote tumor regression in animal models, but only when the inhibition of both pathways is sustained. Transcriptional profiling studies were also used to establish a predictive signature of effective mTORC1/MEK inhibition in vivo. Within this signature, we unexpectedly found that the glucose transporter gene, GLUT1, was potently suppressed but only when both pathways were effectively inhibited. Moreover, unlike VHL and LKB1 mutant cancers, reduction of 18F-FDG uptake measured by FDG-PET required the effective suppression of both mTORC1 and MEK. Together these studies identify optimal and sub-optimal therapeutic targets in NF1-mutant malignancies and define a non-invasive means of measuring combined mTORC1/MEK inhibition in vivo, which can be readily incorporated into clinical trials. 8 samples, in duplicate, 2X vehicle, 2X Rapamycin, 2X PD-0325901, 2X Rapamycin/PD-0325901

2014-07-01 | E-GEOD-57141 | biostudies-arrayexpress

Transcription profiling of human panel of V600E BRAF and RTK-activated tumor cells and xenografts upon MEK inhibition

2009-02-20 | E-GEOD-10086 | biostudies-arrayexpress

Somatic Loss of Wild-Type Kras Enhances Cancer Fitness and Promotes MEK Dependence

Project description:Investigating therapeutic “outliers” that show exceptional responses to anti-cancer treatment can reveal unexpected synthetic lethal interactions and uncover biomarkers of drug sensitivity. Preclinical trials investigating primary murine acute myeloid leukemias (AMLs) generated by retroviral insertional mutagenesis in KrasG12D “knock-in” mice showed that the MEK inhibitor PD0325901 (PD901) extended survival while the pan-phosphoinositide 3-kinase (PI3K) inhibitor GDC-0941 was ineffective. One outlier PD901-treated AML had a four-fold improvement in survival, and exhibited intrinsic drug resistance at relapse. This resistant leukemia arose from an evolutionary precursor of the dominant drug-sensitive AML, and KrasG12D was duplicated in both AML clones. Loss of wild-type (WT) Kras both enhanced the competitive fitness of the dominant clone and rendered it more sensitive to MEK inhibition. Similarly, colorectal cancer cell lines with loss of WT KRAS are more sensitive to MEK inhibitors, and CRISPR-Cas9-mediated replacement of WT KRAS with a mutant allele sensitized a heterozygous mutant HCT116 cells to drug treatment. In a large prospectively characterized cohort of tumors from patients with advanced and metastatic cancers, 642 of 1168 (55%) with KRAS mutations exhibited allelic imbalance. Together, these studies demonstrate that serial genetic changes at the Kras/KRAS locus are frequent in cancer, and can modulate competitive fitness and MEK dependency.

2016-12-22 | GSE92682 | GEO

Gene expression profiling of oncogenic NRAS driven mouse melanomas that have developed resistance to NRAS withdrawal

Project description:Targeted therapies have the potential to revolutionize cancer care by providing personalized treatment strategies that are less toxic and more effective but it is clear that for most solid tumors suppression of a single target is not sufficient to prevent development of resistance. A powerful method to identify mechanisms of resistance and targets for combination therapy is to use an in vivo genetic approach. We have developed a novel retroviral gene delivery mouse model of melanoma that permits control of gene expression post-delivery using the tetracycline (tet)-regulated system. In this study we used this melanoma model to select for resistant tumors following genetic inhibition of mutant NRAS. Analysis of tumors that became resistant to NRAS suppression revealed that the most common mechanism of resistance was overexpression of the Met receptor tyrosine kinase (RTK). Importantly, inhibition of Met overcomes NRAS resistance in this context. Analysis of NRAS mutant human melanoma cells revealed that inhibition of MEK is also associated with adaptive RTK signaling. Furthermore, co-inhibition of RTK signaling and MEK overcomes acquired MEK inhibitor resistance in NRAS mutant melanoma. These data suggest that combined inhibition of RTK and MEK signaling is a rational therapeutic strategy in mutant NRAS driven melanoma. Reversible NRAS Q61R expression in the melanocytes of DCT-TVA;Ink4a/Arf lox/lox mice (FVB/n) was achieved by transducing the animals with Tet-off and TRE-NRASQ61R-IRES-Cre avian leukosis viruses. After tumor initiation, the expression of NRAS Q61R was turned off by administrating doxycycline. Despite initial regression, tumors in 40% of mice developed resistance to NRAS Q61R withdraw. Seven resistant tumors and one control tumor where NRAS Q61R expression was not interrupted were subjected to genome-wide gene expression profiling.

2014-10-31 | E-GEOD-51906 | biostudies-arrayexpress

Gene expression profiling of oncogenic NRAS driven mouse melanomas that have developed resistance to NRAS withdrawal

2014-10-31 | GSE51906 | GEO

ETV2 regulates PARP-1 binding protein to induce ER stress-mediated cell death in tuberin-deficient cells

Project description:Syk inhibitor demonstrates antiproliferative effect on Tsc2-deficient cells and LAM lung nodules similar to rapamycin. A feedback loop between Syk inhibition and mTORC1 inhibition pathways is also present in these Tsc2-deficient cells. We used microarrays to discern the potential difference in Syk inhibition and mTORC1-inhibition pathways. The goal was to investigate regulatory pathways or targets of Syk inhibition to induce cytocidal response in Tsc2-deficient cells, independent of its crosstalk with mTORC1 signaling.

2022-02-14 | GSE183110 | GEO

Reduced Proteolytic Shedding of Receptor Tyrosine Kinases is a Post-Translational Mechanism of Kinase Inhibitor Resistance.

Project description:Expression data from MDA-MB231 human breast cancer cells treated with metalloproteinase inhibitor (10uM BB94), MEK inhibitor (3uM PD325901), or DMSO control shows substantial overlap in the transcriptional responses arising from MEK and protease inhibition, suggesting a shared mechanism of action. Kinase inhibitor resistance often involves upregulation of poorly understood “bypass” signaling pathways. Here, we show that extracellular proteomic adaptation is one path to bypass signaling and drug resistance. Proteolytic shedding of surface receptors, which can provide negative feedback on signaling activity, is blocked by kinase inhibitor treatment and enhances bypass signaling. In particular, MEK inhibition broadly decreases shedding of multiple receptor tyrosine kinases (RTKs) including HER4, MET, and most prominently AXL, an ADAM10 and ADAM17 substrate, thus increasing surface RTK levels and mitogenic signaling. Progression-free survival of melanoma patients treated with clinical BRAF/MEK inhibitors inversely correlates with RTK shedding reduction following treatment, as measured non-invasively in blood plasma. Disrupting protease inhibition by neutralizing TIMP1 improves MAPK inhibitor efficacy, and combined MAPK/AXL inhibition synergistically reduces tumor growth and metastasis in xenograft models. Altogether, extracellular proteomic rewiring through reduced RTK shedding represents a surprising mechanism for bypass signaling in cancer drug resistance.

2016-03-21 | GSE77868 | GEO

BI-3406, a potent and selective SOS1::KRAS interaction inhibitor, is effective in KRAS-driven cancers through combined MEK inhibition

Project description:KRAS is the most frequently mutated driver of pancreatic, colorectal, and non-small cell lung cancers. Direct KRAS blockade has proven challenging and inhibition of a key downstream effector pathway, the RAF-MEK-ERK cascade, has shown limited success due to activation of feedback networks that keep the pathway in check. We hypothesized that inhibiting SOS1, a KRAS activator and important feedback node, represents an effective approach to treat KRAS-driven cancers. We report the discovery of a highly potent, selective and orally bioavailable small-molecule SOS1 inhibitor, BI-3406, that binds to the catalytic domain of SOS1 thereby preventing the interaction with KRAS. BI-3406 reduces formation of GTP-loaded RAS and limits cellular proliferation of a broad range of KRAS-driven cancers. Importantly, BI-3406 attenuates feedback reactivation induced by MEK inhibitors and thereby enhances sensitivity of KRAS-dependent cancers to MEK inhibition. Combined SOS1 and MEK inhibition represents a novel and effective therapeutic concept to address KRAS-driven tumors.

2020-08-20 | GSE128385 | GEO

Paired MEK inhibited and control

2009-02-11 | GSE10087 | GEO