Emergence of RAS or EGFR extracellular domain mutations and duration of response to EGFR blockade in colorectal cancer
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ABSTRACT:
PROVIDER: PRJEB15863 | ENA |
REPOSITORIES: ENA
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Project description:KRAS mutations are the ost abundand driver mutations found in lung adenocarcinoma patients. Unfortunately, there are no clinical approved inhibitors available, to directly target mutant forms of KRAS. The aim of the study was to unravel the impact of upstream Egfr activation in signaling of mutated K-ras. We found that upregulation of G12D mutant Kras induced genes was significantly impaired when Egfr was knocked out. Our data suggests that signaling of mutant Kras depends on upstream activation. This finding may be exploited therapeutically by targeting EGFR in KRAS mutant patients.
2018-08-29 | GSE113146 | GEO
Project description: Not available
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Project description:Inhibition of EGFR signaling downregulates K-RAS mutated activity
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Project description:MAPK scaffolds, such as IQGAP1, assemble pathway kinases together to effect signal transmission and disrupting scaffold function therefore offers a potentially orthogonal approach to MAPK cascade inhibition. Consistent with this possibility, we observed an IQGAP1 requirement in Ras-driven tumorigenesis in mouse and human tissue. Delivery of the IQGAP1 WW peptide sequence that mediates Erk1/4 binding, moreover, disrupted IQGAP1-Erk1/2 interactions, abolished Ras/Raf-driven tumorigenesis, bypassed acquired resistance to the B-Raf inhibitor vemurafinib (PLX- 4032), and acts as a systemically deliverable therapeutic to significantly increase lifespan of tumor bearing mice. Scaffold-kinase interaction blockade (SKIB) acts by a mechanism distinct from direct kinase inhibition and represents a strategy to target over-active oncogenic kinase cascades in cancer. Gene expression profiling: Fragmented cRNA was hybridized to the Mouse Gene 1.0 ST Array (Affymetrix). Iqgap1 wild-type and Iqgap1 knockout mouse treated with topical 4OHT for 0 days and 6 days days are compared.
2013-04-01 | E-GEOD-44967 | biostudies-arrayexpress
Project description:Abstract: RAS-like (RAL) GTPases function in Wnt signalling-dependent intestinal stem cell proliferation and regeneration. Whether RAL proteins work as canonical RAS effectors in the intestine, and the mechanisms of how they contribute to tumorigenesis remain unclear. Here, we show that RAL GTPases are necessary and sufficient to activate EGFR/MAPK signalling in the intestine. We identify non-canonical roles of RAL GTPases not as RAS effectors, but rather by acting upstream of RAS activation via induction of EGFR internalisation . Knocking down Drosophila RalA from intestinal stem and progenitor cells leads to increased levels of plasma membrane-associated EGFR and decreased MAPK pathway activation. Importantly, in addition to impacting stem cell proliferation and damage-induced intestinal regeneration, this function of RAL GTPases drives EGFR-dependent tumorigenic growth in the intestine and in human mammary epithelium. Altogether, our results reveal previously unrecognised cellular and molecular contexts where RAL GTPases become essential mediators of EGFR-driven tissue homeostasis and malignant transformation. Results: RalA is required within ISCs to induce midgut adult midgut regeneration following damage by oral infection with Erwinia carotovora carotovora 15 (Ecc15) (Johansson et al., 2019). To achieve a global view of intestinal pathways affected by RalA, we performed a transcriptomic analysis by RNAseq of whole midguts from vehicle treated (Mock) or damaged (Ecc15 fed) control animals or following RalA knockdown in intestinal stem and progenitor cells using the escargot-gal4 driver (ISC/EB>) (Micchelli and Perrimon, 2006). Consistent with its effect on ISC proliferation (Johansson et al., 2019), RalA knockdown significantly impaired damage-induced upregulation of cell cycle genes in the midgut. Additionally, levels of multiple transcriptional targets of the EGFR/MAPK pathway (Golembo et al., 1996; Hsu et al., 2001; Jin et al., 2015; Meng and Biteau, 2015), such as argos (aos), rhomboid (rho), Sox21a and string (stg) were increased following Ecc15 infection in control midguts. The upregulation of these target genes was significantly impaired upon RalA knockdown.
2021-02-01 | GSE162421 | GEO
Project description:EGFR targeted therapy is in clinical use to treat squamous cell carcinoma of the head and neck and other cancers of lining epithelium. Activating Ras mutations are a negative prognostic factor for response to EGFR ablation therapy in multiple cancer types. Furthermore, the major adverse consequence of this therapy is an acneiform papulopustular eruption on normal skin. To better understand Ras signaling in an EGFR depleted environment, we performed gene expression profiling on oncogenic Ras transformed and wildtype mouse keratinocytes with EGFR ablated chronically by genetic deletion or acutely by drug treatment. We were able to identify a 25 gene signature specific to the Ras-EGFR ablation interaction and a distinct 19 gene EGFR ablation signature on normal keratinocytes. EGFR ablation in the context of wildtype Ras reduces ontologies favoring cell cycle control and transcription while ablation in the context of oncogenic Ras enriches ontologies for ion channels and membrane transporters, particularly focused on calcium homeostasis. The study showed substantial differences in ontologies between chronic EGFR ablation and acute pharmacological ablation, both with and without Ras activation. Pathway and biochemical analysis indicates that activation of p38α is a response to both acute and chronic abrogation of EGFR signaling under conditions of Ras activation. This was confirmed in oncogenic RAS transformed human keratinocytes and in tumors developing in orthografts of EGFR ablated mouse keratinocytes transformed by oncogenic Ras. EGFR ablation in the absence of oncogenic Ras revealed Erk and IL-1β related pathways. These findings reveal previously unrecognized interactions between Ras and EGFR signaling in squamous tumor cells that could influence the therapeutic response to EGFR ablation therapy.
2012-01-11 | GSE29415 | GEO
Project description:We showed that CD8+ T cell-dependent antitumor response was induced by an EGFR-tyrosine kinase inhibitor (TKI) against syngeneic Egfr-mutant NSCLC tumors and that the effect was further pronounced by the sequential dual blockade of PD-1 and vascular endothelial growth factor receptor 2 (VEGFR2).
2023-02-22 | GSE197260 | GEO
Project description:MAPK scaffolds, such as IQGAP1, assemble pathway kinases together to effect signal transmission and disrupting scaffold function therefore offers a potentially orthogonal approach to MAPK cascade inhibition. Consistent with this possibility, we observed an IQGAP1 requirement in Ras-driven tumorigenesis in mouse and human tissue. Delivery of the IQGAP1 WW peptide sequence that mediates Erk1/4 binding, moreover, disrupted IQGAP1-Erk1/2 interactions, abolished Ras/Raf-driven tumorigenesis, bypassed acquired resistance to the B-Raf inhibitor vemurafinib (PLX- 4032), and acts as a systemically deliverable therapeutic to significantly increase lifespan of tumor bearing mice. Scaffold-kinase interaction blockade (SKIB) acts by a mechanism distinct from direct kinase inhibition and represents a strategy to target over-active oncogenic kinase cascades in cancer.
2013-04-01 | GSE44967 | GEO
Project description:Colorectal cancer (CRC) is the third most common cancer world-wide with 1.2 million patients diagnosed yearly. In late stage CRC, the most commonly used targeted therapies are monoclonal antibodies cetuximab and panitumumab, which inactivate EGFR. Recent studies have identified alterations in KRAS and other genes as likely mechanisms of primary and secondary resistance to anti-EGFR antibody therapy. Despite these efforts, additional mechanisms of resistance to EGFR blockade are thought to be present in CRC and little is known about determinants of sensitivity to this therapy. To examine the effect of somatic genetic changes in CRC on response to anti-EGFR antibody therapy, we performed complete exome sequence and copy number analyses of 129 patient-derived tumorgrafts and targeted genomic analyses of 55 patient tumors, all of which were KRAS wild-type. We analyzed the response of tumors to anti-EGFR antibody blockade in tumorgraft models or in clinical settings. In addition to previously identified genes, we detected mutations in ERBB2, EGFR, FGFR1, PDGFRA, and MAP2K1 as potential mechanisms of primary resistance to this therapy. Novel alterations in the ectodomain of EGFR were identified in patients with acquired resistance to EGFR blockade. Amplifications and sequence changes in the tyrosine kinase receptor adaptor gene IRS2 were identified in tumors with increased sensitivity to anti-EGFR therapy. Therapeutic resistance to EGFR blockade could be overcome in tumorgraft models through combinatorial therapies targeting actionable genes. These analyses provide a systematic approach to evaluate response to targeted therapies in human cancer, highlight new mechanisms of responsiveness to anti-EGFR therapies, and provide new avenues for intervention in the management of CRC.
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Project description:Our research data suggest that almost all basal-like tumors have an EGFR-activation profile, however, few may respond to the direct inhibition of EGFR due to ligand independent activation of the EGFR-RAS-MEK pathway via CRYAB or KRAS function. Thus, for those tumors that show a ligand independent EGFR-activation profile, alternative strategies that target downstream components like MEK may prove to be viable alternatives. Keywords: reference x sample
2007-08-20 | GSE6128 | GEO