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Response to ERBB3-Directed Targeted Therapy in NRG1-Rearranged Cancers | Cancer Discovery
Interesting note that NRG1 rearrangements can be oncogenic drivers and ErbB3 blocking Abs can inhibit their effects. erbB2 inhibition was not as effective, intriguingly. List all NRG1 fusions in TCGA.

"NRG1 rearrangements are oncogenic drivers that are enriched in invasive mucinous adenocarcinomas (IMA) of the lung. The oncoprotein binds ERBB3–ERBB2 heterodimers and activates downstream signaling, supporting a therapeutic paradigm of ERBB3/ERBB2 inhibition. As proof of concept, a durable response was achieved with anti-ERBB3 mAb therapy (GSK2849330) in an exceptional responder with an NRG1-rearranged IMA on a phase I trial (NCT01966445). In contrast, response was not achieved with anti-ERBB2 therapy (afatinib) in four patients with NRG1-rearranged IMA (including the index patient post-GSK2849330). Although in vitro data supported the use of either ERBB3 or ERBB2 inhibition, these clinical results were consistent with more profound antitumor activity and downstream signaling inhibition with anti-ERBB3 versus anti-ERBB2 therapy in an NRG1-rearranged patient-derived xenograft model. Analysis of 8,984 and 17,485 tumors in The Cancer Genome Atlas and MSK-IMPACT datasets, respectively, identified NRG1 rearrangements with novel fusion partners in multiple histologies, including breast, head and neck, renal, lung, ovarian, pancreatic, prostate, and uterine cancers.

Significance: This series highlights the utility of ERBB3 inhibition as a novel treatment paradigm for NRG1-rearranged cancers. In addition, it provides preliminary evidence that ERBB3 inhibition may be more optimal than ERBB2 inhibition. The identification of NRG1 rearrangements across various solid tumors supports a basket trial approach to drug development. Cancer Discov; 8(6); 686–95.
NRG1  fusion  ErbB3  ErbB2  blocking_antibody 
january 2019 by Segalllab
Mesenchymal stem cells drive paclitaxel resistance in ErbB2/ErbB3-coexpressing breast cancer cells via paracrine of neuregulin 1 - ScienceDirect
MSCs as a possible source of NRG1 for drug resistance of B2/B3 positive tumor cells - assuming MSCs are part of the TME as described:

"Mesenchymal stem cells (also mesenchymal stromal cells, MSCs) are connective tissue progenitor cells that contribute to fibrotic reactions during tissue remodeling and repair in places of wounding and inflammation. In response to chemokines from tumor cells, MSCs are continuously recruited to and become integral components of the tumour microenvironment [7]. MSCs in tumor microenvironment have been shown to exert influence on multiple hallmarks of cancer including resistance to chemotherapy [8,9]. Therefore, MSCs seem to act as “co-conspirators” within the tumor microenvironment, protecting cancer cells from chemotherapy. However, little has been done to investigate the detrimental effects of MSCs in chemotherapeutic resistance of breast cancers."
mesenchymal_stem_cells  NRG1  paclitaxel-resistance  drug_resistance  ErbB2  ErbB3  breast_cancer 
september 2018 by Segalllab
The brain microenvironment mediates resistance in luminal breast cancer to PI3K inhibition through HER3 activation | Science Translational Medicine
Focusing on ErbB3 in tumor cells and how sensitivity to PI3K inhibition can be increased by blocking ErbB3 signaling - they focus on tumor cells, not clear if some stromal cells might express erbB3 as well. Use ErbB3 Abs, leaving NRG1 alone, although

"Our analysis revealed that NRG-1 is expressed in both the HER2-positive (cancer) and HER2-negative (stromal) cells (fig. S7B) without any significant difference. Together, these data indicate that both stromal and cancer cells within BM express NRG-1 isoforms, and therefore, activation of HER3 can be mediated via autocrine and/or paracrine mechanisms."
breast_cancer  brain  Metastasis  NRG1  ErbB3  PI3K 
september 2017 by Segalllab
Neuregulin-1β induces proliferation, survival and paracrine signaling in normal human cardiac ventricular fibroblasts
cardiac fibroblasts have erbB3 and erbB2 which mediate responses to NRG1B. Example of other stromal cells that might respond to NRG1. No obvious mention of JAG1 but their RNAseq data does not seem to be available.
NRG1  ErbB3  ErbB2  fibroblasts 
july 2017 by Segalllab
ERBB signaling attenuates proinflammatory activation of nonclassical monocytes | Heart and Circulatory Physiology
Studies with human monocytes show ErbB3 and ErbB2 expression and GGF2 stimulation (not sure why theyused that) suppressed TNFalpha expression suggesting that NRG1 reduces inflammatory responses. However in Ramon's microarray NRG1+CSF1 stimulated TNF....

"Our results, demonstrating an inhibitory effect of ERBB3 on proinflammatory activation of CD14lowCD16+ monocytes, add further detail to the concept of NRG as an important modulator of inflammation. Interindividual variability in ERBB3 expression appears to relate to both baseline TNF-α expression in HF as well as the ability of rNRG to suppress LPS-inducible TNF-α expression in vitro in control subjects without HF. We speculate that NRG, acting via ERBB3 receptors to downregulate proinflammatory activation of monocytes, may contribute to prevention of inflammation and progression of HF. Given that the uncontrolled activation of monocytes can lead to severe inflammatory conditions (59), NRG/ERBB signaling in CD14lowCD16+ monocytes may represent a new therapeutic option for the treatment of chronic diseases associated with inflammation, including but not limited to HF"
ErbB2  ErbB3  monocyte  macrophage  macrophage_polarization  GGF2  tnfa 
june 2017 by Segalllab
Oncotarget | Feedback activation of HER3 attenuates response to EGFR inhibitors in colon cancer cells
Both NRG1 and ERbB3 are upregulated in colon cancer line by EGFR inhibitors - perhaps occurs in BC cells as well?
"Here, we observed that all three drugs induced a significant compensatory mRNA upregulation of HER3 within 24h (Figure 2A). Concomitant to this, we also observed an increase in the HER3 ligand heregulin (NRG1) mRNA levels after cetuximab, gefitinib and lapatinib treatments (Figure 2B)"
NRG1  ErbB3  cetuximab  gefitinib  lapatinib  drug_resistance 
april 2017 by Segalllab
Interleukin-6 and neuregulin-1 as regulators of utrophin expression via the activation of NRG-1/ErbB signaling pathway in mdx cells
References to studies that IL6 could induce release of NRG1 from endothelial cells. Oddly they never actually look at NRG1 release in this paper though! Probably challenging to detect released NRG1 - maybe sticks to matrix?

"Studies performed in cultured human vascular endothelial cells have demonstrated that IL-6 induces proteolytic processing of transmembrane NRG, releasing the soluble form that is secreted to the extracellular medium [49].

It has been described that MMPs activity is modulated by intracellular Ca2 + levels [67] ; [68] and that IL-6 induces intracellular Ca2 + transients in cultured C2C12 muscle cells [65]. We explored whether Ca2 + transients induced by IL-6 could be associated to NRG-1 processing, to the early events of NRG-1/ErbB activation and to utrophin induction in mdx myotubes. The results of the experiments carried out in the presence of either an intracellular Ca+ 2 chelator or a wide range MMP inhibitor suggest the involvement of Ca+ 2 in MMPs activation, NRG-1 processing and utrophin induction
NRG1  il6  calcium  utrophin  ErbB3 
april 2017 by Segalllab
Wnt and Neuregulin1/ErbB signalling extends 3D culture of hormone responsive mammary organoids : Nature Communications
Looks like a significant step forward in understanding the interepithelial signaling - I don't think any stromal cell contributions are present here.
"Basal cells secrete Nrg1, resulting in Nrg1/ErbB signalling activation in luminal cells, promoting luminal progenitor cell expansion and differentiation. In contrast, progesterone-stimulated Wnt4 secretion by luminal ER+ cells, alongside R-spondin 1 produced by luminal ER− cells, activate Wnt signalling in the basal stem/progenitor cell population via the Wnt receptors Fz and Lrp5/6 and the R-spondin 1 receptor Lgr5. Wnt signalling activation in this compartment is likely to promote growth and differentiation of the basal cell layer. Fz, frizzled; Lgr5, leucine-rich repeat-containing G-protein-coupled receptor 5; Lrp5/6, low-density lipoprotein receptor-related protein 5/6."
organoid  mammary  gland  NRG1  wnt  ErbB3  ErbB4  luminal_cells  basal_cells 
february 2017 by Segalllab
Novel association of DJ-1 with HER3 potentiates HER3 activation and signaling in cancer | Zhang | Oncotarget
HER3 protein levels are regulated by DJ-1/PARK7 by PARK7 binding HER3 and protecting it from ubiquitination and degradation. Binding of NRG1 stimulates dissociation of PARK7 from HER3 - so there is signaling and degradation.
her3  erbb3  turnover 
december 2016 by Segalllab
The ER structural protein Rtn4A stabilizes and enhances signaling through the receptor tyrosine kinase ErbB3 | Science Signaling
Looking at ErbB3 protein regulation - Rtn4 blocks the ErbB3 ubiquitinase by sequestering in ER tubules, thus increasing ErbB3 levels
erbb3  ubiquitinylation 
october 2016 by Segalllab
Integrated and Functional Genomics Analysis Validates the Relevance of the Nuclear Variant ErbB380kDa in Prostate Cancer Progression. - PubMed - NCBI
I was not sure how to identify all the targets, but potentially interesting promoter sites that ErbB3 binds to as a possible mechanism of gene regulation.
erbb3  nuclear_localization  promoter_binding_sites 
august 2016 by Segalllab
HER3 and its ligand, heregulin, as targets for cancer therapy. - PubMed - NCBI
summary of antibodies and patents on antibodies blocking HER3 mainly and one NRG1 blocker - should look into NRG1 blocking Abs?
erbb3  nrg1  blocking_antibody 
july 2016 by Segalllab
Myofibroblasts have an impact on expression, dimerization and signaling of different ErbB receptors in OSCC cells - Journal of Receptors and Signal Transduction -
The main point for me was that ErbB3 can heterodimerize with the truncated activated form of ErbB2 - p95 HER2. Something to check on if maybe macrophages make this as a splice variant? Does our pcr detect this?

Surprisingly, we detected a heterodimerization between HER3 and p95HER2 which is strongly enhanced by FCMTGFβ.
erbb3  ErbB2  Heterodimer  p95HER2 
july 2016 by Segalllab
Nuc-ErbB3 regulates H3K27me3 levels and HMT activity to establish epigenetic repression during peripheral myelination - Ness - 2016 - Glia - Wiley Online Library
Description of the effect of mutating the nuclear localization signal of ErbB3 on myelination. They claim that it is affecting a specific isoform but I bet it is affecting all nuclear ErbB3 transport. Still it identifies an effect on myelination that may reflect regulation of specific methylation by nuclear ErbB3
erbb3  nuclear_localization  myelination 
july 2016 by Segalllab
Oncogene - ErbB3 upregulation by the HNSCC 3D microenvironment modulates cell survival and growth
they find for hnscc lines that hypoxia in 3D spheroids can induced ErbB3 expression and increased responsiveness to HRG1. Oddly, this seems not be be blocked by lapatinib!
erbb3  spheroid  3D_culture  nrg1  hypoxia 
july 2016 by Segalllab
Interaction with epsin 1 regulates the constitutive clathrin-dependent internalization of ErbB3
although the assay for retention on the surface seems tricky, it is interesting that they show that ErbB3 tends to be constitutively internalized - something we have seen previously on breast cancer cells as well. Perhaps there is a cycling process? not clear if this is true for macrophages....
erbb3  endocytosis  eps1  clathrin 
july 2016 by Segalllab
Synchronized Targeting of Notch and ERBB Signaling Suppresses Melanoma Tumor Growth through Inhibition of Notch1 and ERBB3
Evaluation of inhibition of both ErbB3 and Notch - note also: " In melanoma, we identified neuregulin-1 as a new transcription target of Notch1 (Zhang et al., 2012). Neuregulin-1 produced by Notch1-expressing cells sustains melanoma growth in part by activating ERBB3/ERBB2 signaling that triggers progrowth/survival cues in melanoma cells (Zhang et al., 2013)."
melanoma  erbb3  nrg1  notch  drug_resistance  stem_cells 
june 2016 by Segalllab

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