Associations between AI-assisted tumor amphiregulin and epiregulin IHC and outcomes from anti-EGFR therapy in the routine management of metastatic colorectal cancer
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ABSTRACT:
PROVIDER: PRJEB63103 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR11548100_1.fastq.gz | Fastqsanger.gz | |||
| ERR11548100_2.fastq.gz | Fastqsanger.gz | |||
| ERR11548200_1.fastq.gz | Fastqsanger.gz | |||
| ERR11548200_2.fastq.gz | Fastqsanger.gz | |||
| ERR11548300_1.fastq.gz | Fastqsanger.gz |
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Project description:PurposeHigh tumor production of the EGFR ligands, amphiregulin (AREG) and epiregulin (EREG), predicted benefit from anti-EGFR therapy for metastatic colorectal cancer (mCRC) in a retrospective analysis of clinical trial data. Here, AREG/EREG IHC was analyzed in a cohort of patients who received anti-EGFR therapy as part of routine care, including key clinical contexts not investigated in the previous analysis.Experimental designPatients who received panitumumab or cetuximab ± chemotherapy for treatment of RAS wild-type mCRC at eight UK cancer centers were eligible. Archival formalin-fixed paraffin-embedded tumor tissue was analyzed for AREG and EREG IHC in six regional laboratories using previously developed artificial intelligence technologies. Primary endpoints were progression-free survival (PFS) and overall survival (OS).ResultsA total of 494 of 541 patients (91.3%) had adequate tissue for analysis. A total of 45 were excluded after central extended RAS testing, leaving 449 patients in the primary analysis population. After adjustment for additional prognostic factors, high AREG/EREG expression (n = 360; 80.2%) was associated with significantly prolonged PFS [median: 8.5 vs. 4.4 months; HR, 0.73; 95% confidence interval (CI), 0.56-0.95; P = 0.02] and OS [median: 16.4 vs. 8.9 months; HR, 0.66 95% CI, 0.50-0.86; P = 0.002]. The significant OS benefit was maintained among patients with right primary tumor location (PTL), those receiving cetuximab or panitumumab, those with an oxaliplatin- or irinotecan-based chemotherapy backbone, and those with tumor tissue obtained by biopsy or surgical resection.ConclusionsHigh tumor AREG/EREG expression was associated with superior survival outcomes from anti-EGFR therapy in mCRC, including in right PTL disease. AREG/EREG IHC assessment could aid therapeutic decisions in routine practice. See related commentary by Randon and Pietrantonio, p. 4021.
| S-EPMC10570673 | biostudies-literature
Project description:Mutational status of KRAS in CRC is used to aid patient stratification for Cetuximab treatment. However, only a subset (10-40%) of patients with wt KRAS respond. We analyzed 40 mCRC tumors for Cetuximab response using a functional ex vivo platform. In the subset of non-responsive tumors, mutational (KRAS/BRAF and PIK3CA) and expression (AREG/EREG) analysis of key genes, transcriptomic profiling and GSEA were carried out to elucidate the molecular mechanisms underlying the response. Our analysis revealed deregulation of multiple pathways, notably Notch and Erbb2 and combined blockade of these two nodes elicited significant antitumor response. These findings collectively indicate the dependence of Cetuximab insensitive mCRC tumors on Notch and Erbb2 for survival and progression. 8 Primary tumors tested in ex vivo platform for response to Cetuximab were subjected to expression analysis
2014-04-01 | E-GEOD-56386 | biostudies-arrayexpress
Project description:Mutational status of KRAS in CRC is used to aid patient stratification for Cetuximab treatment. However, only a subset (10-40%) of patients with wt KRAS respond. We analyzed 40 mCRC tumors for Cetuximab response using a functional ex vivo platform. In the subset of non-responsive tumors, mutational (KRAS/BRAF and PIK3CA) and expression (AREG/EREG) analysis of key genes, transcriptomic profiling and GSEA were carried out to elucidate the molecular mechanisms underlying the response. Our analysis revealed deregulation of multiple pathways, notably Notch and Erbb2 and combined blockade of these two nodes elicited significant antitumor response. These findings collectively indicate the dependence of Cetuximab insensitive mCRC tumors on Notch and Erbb2 for survival and progression.
2014-04-01 | GSE56386 | GEO
Project description:Members of the epidermal growth factor family play important roles in the regulation of cell growth, proliferation, and survival. However, the specific roles of each epidermal growth factor family member with respect to brain injury are not well understood. Gene chip assay screens have revealed drastic increases in the expression of the epidermal growth factor family members amphiregulin and epiregulin following lipopolysaccharide stimulation, which activates an immune response. Both immune activity and endoplasmic reticulum stress are activated during cerebral ischemia. We found that the expression levels of amphiregulin and epiregulin were significantly increased under conditions of cerebral ischemia. Because endoplasmic reticulum stress increased the expression of amphiregulin and epiregulin in glial cells, endoplasmic reticulum stress may be a key mediatory factor of pathophysiological activity. Recombinant epiregulin and amphiregulin proteins effectively inhibited endoplasmic reticulum stress and the subsequent induction of neuronal cell death. Therefore, the upregulation of the epidermal growth factor family members epiregulin and amphiregulin may play a critical role in preventing endoplasmic reticulum stress-induced cell death, thus providing a potential therapy for brain injury.
| S-EPMC4326420 | biostudies-literature
Project description:Cellular senescence is an irreversible growth arrest with a highly dynamic secretome, termed the senescence-associated secretory phenotype (SASP). Senescence has been implicated in somatic reprogramming to pluripotency. The cell-intrinsic proliferation arrest is a barrier for reprogramming, whereas the SASP facilitates the cell fate conversion in nonsenescent cells. However, the mechanisms by which reprogramming-induced senescence regulates cell plasticity are not well understood. Here, we have further investigated how the heterogeneity of paracrine senescence impacts reprogramming. We show that senescence promotes in vitro reprogramming in a stress-dependent manner. We identified a catalog of SASP factors and pathways potentially involved in the cell fate conversion using an unbiased proteomic analysis. Amphiregulin (AREG), a growth factor frequently secreted by the senescent cells, promotes in vitro reprogramming by accelerating proliferation and MET via the EGFR signaling pathway. Of note, AREG treatment diminished the negative effect of donor age on reprogramming. Finally, AREG enhances in vivo reprogramming in the skeletal muscle. Hence, senescence could facilitate cellular plasticity via various SASP factors to promote reprogramming and tissue repair.
2022-07-28 | PXD028590 | Pride
Project description:Background: The gonadotropin-induced resumption of oocyte meiosis in preovulatory follicles is preceded by expression of epidermal growth factor (EGF)-like peptides, amphiregulin (AREG) and epiregulin (EREG), in mural granulosa and cumulus cells. Both the gonadotropins and the EGF-like peptides possess the capacity to stimulate resumption of oocyte meiosis in vitro via activation of a broad signaling network in cumulus cells. To better understand the rapid genomic actions of gonadotropins (FSH) and EGF-like peptides, we analyzed transcriptomes of cumulus cells at 3 h after their stimulation. Methods: We hybridized aRNA from cumulus cells to a pig oligonucleotide microarray and compared the transcriptomes of FSH- and AREG/EREG-stimulated cumulus cells with untreated control cells and vice versa. The identified over- and underexpressed genes were subjected to functional genomic analysis according to their molecular and cellular functions. The expression pattern of 50 selected genes with a known or potential function in ovarian development was verified by real-time qRT-PCR. Results: Both FSH and AREG/EREG increased the expression of genes associated with regulation of cell proliferation, cell migration, blood coagulation and extracellular matrix remodeling. FSH alone induced the expression of genes involved in inflammatory response and in the response to reactive oxygen species. Moreover, FSH stimulated the expression of genes closely related to some ovulatory events either exclusively or significantly more than AREG/EREG (AREG, ADAMTS1, HAS2, TNFAIP6, PLAUR, PLAT, and HSD17B7). In contrast to AREG/EREG, FSH also increased the expression of genes coding for key transcription factors (CEBPB, FOS, ID1/3, and NR5A2), which may contribute to the differing expression profiles of FSH- and AREG/EREG-treated cumulus cells. Conclusions: The impact of FSH on cumulus cell gene transcription was higher than the impact of EGF-like factors in terms of the number of cell functions affected as well as the number of over- and underexpressed genes. Both FSH and EGF-like factors overexpressed genes involved in the post-ovulatory switch in steroidogenesis and tissue remodelling. However, FSH was remarkably more efficient in the up-regulation of several specific genes essential for ovulation of matured oocytes and also genes that been reported to play an important role in maturation of cumulus-enclosed oocytes in vitro.
2015-09-30 | GSE64858 | GEO
Project description:Interventions: Single arm study to explore the efficacy of cetuximab in combination with Irinotecan based treatment in advanced stage RAS/BRAF wild type right sided colorectal cancer with high AREG/EREG expression.
Dosing regimens include either of the following standard of care regimens for the administration of cetuximab in combination with Irinotecan. They will be chosen at physician discretion;
1) Cetuximab 500mg/m2 Intravenous infusion Day 1 of a 14 day cycle in combination with Irinotecan Intravenous infusion 180mg/m2 Day 1 of a 14 day cycle until disease progression, unacceptable toxicity or withdrawal of consent.
2)Cetuximab 500mg/m2 Intravenous infusion Day 1 of a 14 day cycle in combination with Irinotecan Intravenous infusion 180mg/m2 Day 1 of a 14 day cycle AND Calcium folinate 50mg Intravenous bolus Day 1, Fluorouracil 400mg/m2 Intravenous infusion on Day 1 followed by continuous intravenous infusion Fluorouracil 2400mg/m2 pump over 46 hours until disease progression, unacceptable toxicity or withdrawal of patient consent.
Archival tumour tissue from advanced colorectal cancer patients will be tested using an immunohistochemistry assay for Amphiregulin/epiregulin (AREG/EREG)to determine a population of patients who may benefit from this combination of therapy.
Participants will be asked to consent to pre- screening of their archival samples for the purpose of AREG/EREG testing. Once consented, testing of archival tissue may take place at any point during the participants first line treatment. There is no time limit for testing results and being considered eligible for the main study. Once AREG/EREG testing results have been received by the site Investigator ,if clinically appropriate the main study participant information and consent form (PICF) will be o
Primary outcome(s): To determine progression free survival (PFS) of patients with right-sided, RAS/BRAF wild-type advanced Colorectal Cancer (CRC ) with high AREG/EREG expression (AREG/EREG high) following treatment with cetuximab + irinotecan based treatment in the second or later line setting. Progression Free Survival will be assessed by CT Chest/Abdomen/Pelvis (or MRI for participants unable to receive contrast) at 8 week intervals during the treatment phase, and at End of Treatment or until disease progression.[Disease status will be assessed at the following time points; CT scan with IV contrast (or MRI for participants unable to receive contrast) every 8 weeks during treatment phase, until disease progression or cessation of treatment for other reasons : ie: patient choice, unacceptable toxicity. Disease status will be accessed within 4 weeks of the last dose of treatment. After a patient has progressed on study treatment, no further study specific follow-up assessments will be required. All patients will be followed until death or study completion, to collect details of any further treatment and survival status.]
Study Design: Purpose: Treatment; Allocation: Non-randomised trial; Masking: Open (masking not used);Assignment: Other;Type of endpoint: Efficacy
| 93851 | ecrin-mdr-crc
Project description:In this study, we demonstrate that radiation induces the epidermal growth factor receptor (EGFR) ligand amphiregulin (AREG) in tumor cells, which stimulates distant metastasis proliferation in both patients and pre-clinical murine tumor models. Using single-cell RNAseq (sc-RNAseq), we characterized the effects of AREG-induction on immune cells in the lung metastatic microenvironment of B6 mice.
2025-02-27 | GSE250375 | GEO
Project description:Epidermal growth factor receptor (EGFR) and its ligands amphiregulin (AREG) and epiregulin (EREG) play a central role in the development of colorectal cancer, but the prognostic values of AREG and EREG are controversial. We conducted a meta-analysis of studies that investigated AREG and/or EREG mRNA levels in primary tumors to determine their prognostic value in metastatic colorectal cancer (mCRC). In addition, RAS status was assessed. Relevant articles were identified by searching the EMBASE, PubMed, and Cochrane Library databases. Hazard ratios (HR) with 95% confidence intervals (CIs) were calculated using a random-effects model. Nine studies involving 2167 patients were included in this meta-analysis. High AREG expression was associated with longer overall survival (OS) and progression-free survival (PFS). High EREG expression was also associated with prolonged OS and PFS. In RAS wild-type (WT) patients who received anti-EGFR therapy, high AREG and EREG expression was associated with longer OS. Our results indicate that high AREG and EREG mRNA expression are independent favorable prognostic biomarkers in mCRC. The expression of these ligands should be considered when evaluating prognoses in RAS-WT patients receiving anti-EGFR therapy.
| S-EPMC5342459 | biostudies-literature
Project description:We analyzed the effect of tetracycline (Tet)-inducible amphiregulin (AREG) silencing on the transcriptome of immortalized human N/TERT keratinocytes in the presence or absence of exogenous rhEGF. Tetracycline-mediated AREG silencing significantly altered the expression of 2,331 genes, 623 of which were not normalized towards normal by treatment with EGF. Genes irreversibly up-regulated by suppression of AREG overlapped with genes involved in keratinocyte differentiation. A significant proportion of the irreversibly down-regulated genes featured upstream binding sites recognized by FoxM1
2016-06-23 | GSE70230 | GEO