Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA143749 | ENA |
REPOSITORIES: ENA
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Project description:The ERBB family consists of four receptors (EGFR, ERBB2, ERBB3, and ERBB4) that are critical in normal development and physiology of mammalian gastrointestinal epithelial tissues. Amplifications or mutations in ERBB2 are commonly found in CRC, suggesting a possible therapeutic target. Patients with ERBB2-amplification in breast and gastroesophageal cancer are routinely treated with the ERBB2-directed antibody trastuzumab. However, ERBB2 is not commonly targeted in clinical practice of treating CRC. Notably, ERBB2 status could guide therapy as a negative marker for EGFR-targeted therapy (cetuximab) and identify likely responders for ERBB2-directed therapy. Although the most common marker for negative efficacy of anti-EGFR therapy is KRAS mutations, many patients with KRAS wild-type tumors do not respond to EGFR inhibition. As the primary EGFR-directed antibodies for CRC do not inhibit ERBB2, alterations increasing ERBB2 may serve as a superior negative predictor of EGFR therapy since previous studies demonstrate that ERBB2 amplification confers resistance to cetuximab in preclinical models. Despite the compelling evidence, the utility of ERBB2 as a target for molecular therapy of primary CRC tumors in preclinical models is largely unexplored. As such, our goal is to further characterize the influece of ERBB2 in the initiation and progression of CRC.
2024-08-16 | GSE241084 | GEO
Project description:Aberrant activation of signaling pathways controlled in normal epithelial cells by the epidermal growth factor receptor (EGFR) has been linked to cetuximab (a monoclonal antibody against EGFR) resistance in head and neck squamous cell carcinoma (HNSCC). To infer relevant and specific pathway activation downstream of EGFR from gene expression in HNSCC, we generated gene expression signatures using immortalized keratinocytes (HaCaT) subjected to either ligand stimulation or pharmacological inhibition of the signaling intermediaries PI-3-Kinase and MEK or transfected with EGFR, RELA/p65, or HRASVal12. The gene expression patterns that distinguished the various HaCaT variants and conditions were inferred using the Markov chain Monte Carlo (MCMC) matrix factorization algorithm Coordinated Gene Activity in Pattern Sets (CoGAPS). This approach inferred gene expression signatures with greater relevance to cell signaling pathway activation than the expression signatures inferred with standard linear models. Furthermore, the pathway signature generated using HaCaT-HRASVal12 further associated with the cetuximab treatment response in isogenic cetuximab-sensitive (UMSCC1) and -resistant (1CC8) cell lines. Our data suggest that the CoGAPS algorithm can generate gene expression signatures that are pertinent to downstream effects of receptor signaling pathway activation and potentially be useful in modeling resistance mechanisms to targeted therapies. 58 total RNA collected from HaCaT cell lines with combinations of the following experimental conditions: forced expression of EGFR, RELA/p65, and HRAS-VAL12D; grown in PBS, serum starve, and media stimulated with TNF or EGF; treated with gefitinib, LY294002, and U1026.
2012-05-22 | E-GEOD-32975 | biostudies-arrayexpress
Project description:Cetuximab (Erbitux) is an antibody drug against EGFR and commonly used in late stage HNSCC and metastatic colorectal cancer. The oncogenic mutation of certain genes are known to drive Cetuximab resistance such as K-RAS or b-RAF mutation. The aberrant activation of signaling pathways in the presence of Cetuximab treatment to overcome cellular stress contribute to acquired resistance to Cetuximab as well. To better understand the mechanisms and molecular patterns of Cetuximab resistant cells, the Cetuximab resistant cells are trained for examining the gene expression profile. The gene expression array is used for identify the molecular signature governing the Cetuximab resitance.
2017-03-02 | GSE63916 | GEO
Project description:Anti-EGFR antibodies are effective in therapies for late-stage colorectal cancer (CRC); however, many tumours are unresponsive or develop resistance. We performed genomic analysis of intrinsic and acquired resistance to anti-EGFR therapy in prospectively collected tumour samples from 25 CRC patients receiving cetuximab (an EGFR inhibitor). Of 25 CRC patients, 13 displayed intrinsic resistance to cetuximab; 12 were intrinsically sensitive. We obtained six re-biopsy samples at acquired resistance from the intrinsically sensitive patients. NCOA4–RET and LMNA–NTRK1 fusions and NRG1 and GNAS amplifications were found in intrinsic-resistant patients. In cetuximab-sensitive patients, we found KRAS K117N and A146T mutations in addition to BRAF V600E, AKT1 E17K, PIK3CA E542K, and FGFR1 or ERBB2 amplifications. The comparison between baseline and acquired-resistant tumours revealed an extreme shift in variant allele frequency of somatic variants, suggesting that cetuximab exposure dramatically selected for rare resistant subclones that were initially undetectable. There was also an increase in epithelial-to-mesenchymal transition at acquired resistance, with a reduction in the immune infiltrate. Furthermore, characterization of an acquired-resistant, patient-derived cell line showed that PI3K/mTOR inhibition could rescue cetuximab resistance. Thus, we uncovered novel genomic alterations that elucidate the mechanisms of sensitivity and resistance to anti-EGFR therapy in metastatic CRC patients.
2019-09-21 | E-MTAB-8340 | biostudies-arrayexpress
Project description:Aberrant activation of signaling pathways controlled in normal epithelial cells by the epidermal growth factor receptor (EGFR) has been linked to cetuximab (a monoclonal antibody against EGFR) resistance in head and neck squamous cell carcinoma (HNSCC). To infer relevant and specific pathway activation downstream of EGFR from gene expression in HNSCC, we generated gene expression signatures using immortalized keratinocytes (HaCaT) subjected to either ligand stimulation or pharmacological inhibition of the signaling intermediaries PI-3-Kinase and MEK or transfected with EGFR, RELA/p65, or HRASVal12. The gene expression patterns that distinguished the various HaCaT variants and conditions were inferred using the Markov chain Monte Carlo (MCMC) matrix factorization algorithm Coordinated Gene Activity in Pattern Sets (CoGAPS). This approach inferred gene expression signatures with greater relevance to cell signaling pathway activation than the expression signatures inferred with standard linear models. Furthermore, the pathway signature generated using HaCaT-HRASVal12 further associated with the cetuximab treatment response in isogenic cetuximab-sensitive (UMSCC1) and -resistant (1CC8) cell lines. Our data suggest that the CoGAPS algorithm can generate gene expression signatures that are pertinent to downstream effects of receptor signaling pathway activation and potentially be useful in modeling resistance mechanisms to targeted therapies.
2012-05-23 | GSE32975 | GEO
Project description:We deciphered molecular mechanisms associated with acquired resistance to anti-EGFR targeted therapy in head and neck squamous cell carcinoma (HNSCC) by comparing gene expression profiles in cetuximab-sensitive and -resistant patient-derived xenograft (PDX) models of HNSCC. We generated and validated several HNSCC PDX models. Resistance mechanisms to anti-EGFR therapy were investigated in one of these PDX models (UCLHN04). First, sensitivity to cetuximab treatment was tested. This model showed high sensitivity to this drug. We induced acquired resistance to anti-EGFR therapy in this sensitive model by treating it chronically with anti-EGFR monoclonal antibody (cetuximab, 30 mg/kg/week) until resistance ensues. RNA-seq analysis was performed on samples coming from untreated and cetuximab-resistant PDX, revealing major changes of expression at the mRNA level.
2024-11-08 | GSE235417 | GEO
Project description:Synthetic activation of chimeric EGFR-Erbb2 receptors causes nuclear translocation of the heterodimers at long time scales. To identify genomic loci bound by nuclear EGFR-Erbb2, chromatin from an MCF10A-5E clone coexpressing chimeric EGFR and Erbb2 was prepared with or without synthetic activation and immunoprecipitated for chimeric EGFR by its GluGlu epitope tag.
2023-03-22 | GSE216242 | GEO
Project description:Recent progress in dissecting molecular mechanisms essential for the survival and propagation of cancer cells triggered rapid development of targeted therapies. Although many of these therapies produce impressive initial responses in tumor suppression, the onset of resistance is practically unavoidable. One of the main approaches for preventing this refractory condition relies on the development of effective combination therapies. Unfortunately, selection of optimal targets for combinatorial treatments is often confounded by limitations in our understanding of tumor biology. Here, we describe an unbiased comprehensive strategy that combines ex-vivo shRNA-based genome wide screening, proteomic profiling using BioID and patient tumor sequencing data analyses to overcome current challenges in identifying the best fit co-targeting agents. Integrating these strategies, we selected EGFR and EPHA2 receptors as molecules of choice for co-targeting in cancer cells, and generated a bispecific fully humanized anti-EGFR/EPHA2 antibody with druggable bioanalytical properties that very effectively suppresses tumor growth compared to its prototype therapeutic anti-EGFR antibody, cetuximab. Despite the overactivation of EGFR signaling in multiple malignancies, the therapeutic applicability of cetuximab is limited due to frequent resistance and could benefit from being used in a combination with another targeted compound. Our analysis indicates that EGFR and EPHA2 expression positively correlate in various cancer types and thus, are available for co-targeting in most tumors. Therefore, our work not only presents an efficient unbiased strategy for selecting optimal targets for combination therapies, but also describes a novel bispecific antibody, which has a high potential for being developed into a new clinically-relevant biologics effective in a broad variety of malignancies.
2023-01-27 | PXD023034 | Pride
Project description:EGFR blockade by the monoclonal antibodies cetuximab or panitumumab causes objective tumor regressions in selected patients with metastatic colorectal cancer (mCRC). However, residual disease reservoirs almost invariably remain even after maximal response to therapy, leading to treatment failure and tumor relapse. Using mCRC patient-derived xenografts (PDXs), we observed that residual cancer cells surviving EGFR inhibition exhibited gene expression patterns reminiscent of a quiescent subpopulation of normal intestinal secretory precursors with Paneth-cell traits. These drug-tolerant cells had reduced expression of EGFR-activating ligands, consistent with lower EGFR dependence, and displayed higher HER2/HER3 pathway activity and persistent PI3K signaling. Mechanistically, cell fate reprogramming towards the Paneth cell-like phenotype was mediated by inactivation of YAP – a master regulator of intestinal epithelium recovery after injury – following cetuximab-induced neutralization of the MAPK cascade. Clinically, tumors from patients in whom cetuximab was not effective were enriched for markers of secretory commitment/Paneth-cell differentiation. In PDX therapeutic experiments, Pan-HER antibodies minimized residual disease burden and induced long-term tumor control after treatment discontinuation. We propose that tolerance to EGFR inhibition in CRC is typified by the adaptive disengagement of an in-built lineage program that jointly drives intestinal regenerative signaling and tumorigenesis. Further, our findings motivate therapeutic strategies to pre-emptively target residual disease before acquisition of irreversible resistance.
2020-05-06 | GSE108277 | GEO
Project description:Despite advances in surgery and radiotherapy of uveal melanoma (UM), many patients develop distant metastases that poorly respond to therapy. Improved therapies for the metastatic disease are therefore urgently needed. Expression of the epidermal growth factor receptor (EGFR), a target of kinase inhibitors and humanized antibodies in use for several cancers, had been reported. 48 human UMs were analyzed by expression profiling. Evidence for signaling in tumors was obtained through the application of a UM-specific EGF signature. The EGFR specific kinase inhibitor, Gefitinib, and the humanized monoclonal antibody, Cetuximab, were tested for their effect on EGFR signaling. Natural killer cell mediated antibody-dependent cellular cytotoxicity (ADCC) and TNF-alpha release was analyzed for Cetuximab. EGFR appears suited as a novel molecular drug target for therapy of uveal melanoma. Gene expression profiles of 19 unique samples from uveal melanoma patients were measured.
2013-11-18 | E-GEOD-51880 | biostudies-arrayexpress