AREG expression

P2, N=29, Recruiting, Australasian Gastrointestinal Trials Group | Not yet recruiting --> Recruiting

Collectively, this study revealed the role and mechanism of AREG in negative immune regulation, and targeting AREG might be a novel immunotherapy for LSCC.

This study highlights the significant role of AREG upregulation in CRC cells in initiating chemotherapeutic resistance to 5-FU under Visfatin stimulation. These findings provide a deeper understanding of drug resistance development in CRC under obese conditions and offer new insights into the correlation between an abnormal increase in AREG levels and the development of 5-FU-resistance in CRC cells, which should be considered in future clinical applications.

Bioinformatics analysis confirmed significant upregulation of AREG in ESCC compared with normal tissues. These findings suggest that AREG plays a crucial role in CAF-mediated ESCC progression and could be a novel therapeutic target for ESCC.

Finally, we demonstrated that in lung adenocarcinoma patients, high expression of AREG and EGFR mutations were mutually exclusive. In conclusion, these data 1) highlight EGFR ligand AREG as a driver of tumor growth in some EGFRWT NSCLC models, 2) illustrate the preclinical efficacy of amivantamab in ligand-driven EGFRWT NSCLC, and 3) identify AREG as a potential predictive biomarker for amivantamab activity in EGFRWT NSCLC.

Macrophages form an important component of VS stroma. scRNAseq reveals three distinct subsets of macrophages in the VS tissue which may have differing roles in the pathogenesis of VS.

In RAS wt mCRC patients receiving EGFR-targeted therapy, BRAF mutation is a powerful prognostic and therapy-predictive biomarker, with no effect found for PIK3CA mutation, PTEN mutation or deletion, but the combined biomarker KRAS/NRAS/BRAF/PIK3CA mutations predict resistance to anti-EGFR therapy. Low miR-31-3p expression may have positive prognostic and therapy predictive effects. Evidence on the prognostic and predictive roles of EGFR and its ligands, and HER2/3/4 is insufficient.

AREG-activated NF-κB and MAPKs signaling, and together with NF-κB and MAPKs inhibitors, AREG significantly reduced the protein expression of iNOS and COX-2. AREG plays a role in hepatic inflammation by increasing iNOS and COX-2 expression via NF-κB and MAPKs signaling.

Finally, Laxiflorin B-4, a C-6 analog of Laxiflorin B, exhibited higher binding affinity for ERK1/2 and stronger tumor suppression. These findings provide a new approach to tumor inhibition using natural anticancer compounds.

P2, N=29, Not yet recruiting, Australasian Gastrointestinal Trials Group

RNA interference of human amphiregulin (AREG) expression in human urinary bladder cell lines T24 and UMUC3 decreased expression of AREG and its 6 target genes and decreased cell proliferation. These data suggest that Areg has an important role in DMA-induced rat bladder carcinogenesis.

No impact on tumour regression was seen with pan. Further testing and safety assessment is warranted.

High 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.

When the tumor of the cohort reached an average volume of 250mm3, mice were treated or not with cetuximab...HER3 targeting (by means of the novel antibody drug conjugate patritumab deruxtecan) and AREG/EREG silencing strongly affected cell viability, suggesting that sensitive models rely on these pathways for their growth.ConclusionWe identified a subset of GEA sensitive to EGFR targeting drugs and propose HER3 and AREG/EREG expression as markers for patients' selection. Further validation on GEA samples derived from clinical trials evaluating effectiveness of EGFR targeting is needed. We believe that, despite the negative results of clinical trials so far, EGFR can represent a suitable target in molecularly selected GEA patients.

P1/2, N=54, Completed, Hellenic Cooperative Oncology Group | Active, not recruiting --> Completed | Trial primary completion date: Jun 2023 --> Jun 2022

TRG-AS1 knockdown markedly reduced the number of TRAP+ cells and the percentage of Ki-67+ cells and decreased E-cadherin expression in xenograft tumor mice. In summary, TRG-AS1 acts an endogenous RNA, inhibited breast cancer bone metastasis by competitively binding with miR-877-5p to upregulate WISP2 expression.

Our study demonstrated different effects on the TME reshaping by sorafenib and lenvatinib. Additionally, enhanced expression of AREG might contribute to attenuation of antitumor immunity in sorafenib treatment. 1012

Understanding the normal and pathological roles of AREG and elucidating the molecular and cellular mechanisms of AREG regulation of ovarian functions will inform innovative approaches for fertility regulation and the prevention and treatment of ovarian diseases. Therefore, this review summarizes the functional roles of AREG in ovarian function and disease.

In co-culture of osteoblasts and fixed PC3 cells, the phosphorylation of EGFR and ERK and subsequent Ptgs2 expression and PGE production were increased, an effect that was attenuated by treatment with inhibitors of EGFR and ERK. These results indicate that membrane-bound TGF-α enhances ERK signaling while also inducing PGE-mediated bone formation in osteoblasts, thus suggesting that prostate cancer regulates both PGE-mediated bone resorption and bone formation at the site of bone metastasis of prostate cancer.

AI assisted IHC evaluation of tumor AREG/EREG expression predicted benefit from anti-EGFR therapy in a retrospective analysis of the PICCOLO trial of second-line irinotecan ± panitumumab... Patients (pts) with available archival FFPE tumor tissue who received panitumumab or cetuximab ± chemotherapy at any time for treatment of mCRC at 8 UK cancer centers were eligible... High tumor AREG/EREG expression was associated with significantly prolonged PFS, OS and DCR among a cohort of pts treated with anti-EGFR therapy during routine care of mCRC. The prognostic effect observed validates the predictive effect of AREG/EREG seen in the PICCOLO trial, where AREG/EREG had no prognostic effect in patients receiving chemotherapy alone. A prospective biomarker-led trial is in set-up to support the use of AREG/EREG IHC in clinical practice.

In summary, we found that CD4+ T cell-derived Areg contributes to CD4+ T cell proliferation after activation, leading to increased T cell expansion, tissue damage, and GVHD-related mortality after allo-BMT. Careful inhibition of the T cell Areg/EGFR axis may represent a novel therapeutic target for prevention or amelioration of GVHD.

According to the hypothesis, we detected the accumulation of AREG in the nucleus of SK-Mel-28-VR, which was cultured under Vemurafenib (VR) selection pressure, and this correlates with JARID1B expression. Here, knockdown of AREG makes the previously resistant cells more sensitive to VR treatment, resulting in inhibited proliferation. Taken together, we suggest that nuclear AREG affects a slow-cycling phenotype and increases resistance to VR, raising a possibility that AREG might be a potential therapeutic target for resistance in melanoma.

Using 370 specimens from 10 tumor types (as well as normal controls), we demonstrate that cleaved amphiregulin is widely expressed in solid tumors and is especially common (> 50% of cases) in breast, prostate, liver and lung cancer. As a potential companion diagnostic for this antibody-drug conjugate, this assay allows identification of tumors with high levels of the cleaved amphiregulin target.

P1/2, N=54, Active, not recruiting, Hellenic Cooperative Oncology Group | Trial completion date: Jul 2022 --> Jul 2023 | Trial primary completion date: Jun 2022 --> Jun 2023

Material and Methods 5×10 6 cells of ID8; ID8 p53 -/-, ID8 p53 -/- R175H and ID8 p53 -/- R273H were injected into C57BL/6 female mice, followed by 6 weeks of injections with anti-AREG (AR37) and anti-PD-L1 (Avelumab) 400µg/ mouse, twice a week...Conclusion Elucidating the varied response of EOC to monotherapies, we aim at evaluating an anti-AREG antibody in conjunction with PD-L1 therapy for synergistic effect. Our aim is to develop a safe and efficacious combinatorial therapy addressing the complexity of AREG and PD-L1 expression in EOC onset and progression.

The results predicted that AREG-EGFR signaling, which is required for tumor growth and survival, might be activated in the cell line in a cell-autonomous manner. As AREG expression is associated with EGFR-targeted drug resistance, this cell line might assist with the identification of novel strategies for MEC treatment.

Interfering with ERK using pharmacological inhibitors prevents AREG upregulation in microglia and microglia-stimulated GL261 invasion. These data highlight AREG as a key factor in produced by tumor associated microglia in promoting glioma invasion.

Materials and The GSTTC study is a non-profit, Italian, multicentre, phase III factorial trial in which 414 patients with loco-regionally advanced Head and Neck Squamous Cell Carcinomas (LAHNSCC) were randomized to receive radiotherapy plus concomitant chemotherapy or cetuximab, preceded or not by induction docetaxel, cisplatin and 5- fluorouracil (TPF). HPV positivity and bcl-2 overexpression significantly correlated with PFS and OS in LAHNSCC. It is of interest the role of PD-L1 as, in its absence, immunotherapy loses most of its effectiveness while chemotherapy, in the context of PD-L1 negative cells, acquires the maximum ability to kill cancer cells.

Moreover, the results indicated that the expression and activation of AREG was also related to 5‑FU resistance, but propofol ameliorated 5‑FU drug resistance. Therefore, the present study suggested that propofol combination therapy may serve as an effective treatment strategy for OSCC.

In summary, we found that CD4 + T cell-derived Areg contributes to their proliferation after activation, leading to increased T cell expansion, tissue damage and GVHD-related mortality after allo-BMT. Careful inhibition of the Areg-EGFR axis in T cells may represent a novel therapeutic target for prevention or amelioration of GVHD.

P1/2, N=54, Active, not recruiting, Hellenic Cooperative Oncology Group | Recruiting --> Active, not recruiting | Trial completion date: Sep 2021 --> Jul 2022 | Trial primary completion date: Sep 2021 --> Jun 2022

Long-term mitochondrial inhibitor treatments-mediated mitochondrial stress adaptation could induce letrozole resistance...Moreover, mitochondrial stress adaptation-increased intracellular levels of reactive oxygen species (ROS) and calcium were shown to induce AREG expression and secretion. In conclusion, our results support the claim that mitochondrial stress adaptation contributes to AI resistance via ROS/calcium-mediated AREG-ERα loop signaling and provide possible treatment targets for overcoming AI resistance.

Amphiregulin did not help in distinguishing enchondromas from low-grade chondrosarcomas. The present study is the first to document the expression of this immunohistochemical marker in enchondromas. Furthermore, amphiregulin expression in enchondromas was localized in short bones, indicating a phenotypic distinction from that in long bones. This distinction may contribute to an improved understanding of the pathogenesis of these lesions.

Finally, OSCC-associated mutant DDX3 increased the expression of AREG, emphasizing the role of DDX3 in tumor progression via SRP-dependent, endoplasmic reticulum-associated translation. Therefore, pharmacological targeting of DDX3 may inhibit the tumor-promoting functions of the TME.

In conclusion, our study discovered two novel severe-disease-specific monocyte subsets as potential predictors and therapeutic targets for severe COVID-19. Overall, this study provides potential predictors for severe disease and therapeutic targets for COVID-19 and thus provides a resource for further studies on COVID-19.

Consistent with these observations, analysis of OvCa patients revealed that high AREG correlates with poor prognosis of patients expressing wildtype TP53. In conclusion, clinical tests of the novel antibody are warranted; high AREG, normal TP53, and reduced CXCL1 activity might identify patients with OvCa who may derive therapeutic benefit.

High Amphiregulin and PTEN expression levels and low P21 expression levels were associated with better response to anti-EGFR therapy and improved survival outcome. They might be considered predictive markers of response to anti-EGFR therapy in mCRC. .