Erb-b2 Receptor Tyrosine Kinase Research Articles

Tyrosine Kinase Receptor ErbB4 in Advillin-Positive Neurons Contributes to Inflammatory Pain Hypersensitivity in Mouse DRG.

Inflammatory pain is a common type of pathological pain. Although the dorsal root ganglion (DRG) is key to pathogenesis of inflammatory pain, the underlying specific molecular and cellular mechanisms remain unclear. In this study, we used mouse models of acute or chronic inflammatory pain, induced by formalin or complete Freund' s adjuvant (CFA), respectively, to explore whether tyrosine kinase receptor ErbB4 participates in the pathogenesis of inflammatory pain. Firstly, we found that both the expression of Neuregulin 1 (Nrg1) and phosphorylation of ErbB4 receptor were upregulated in DRG after inflammatory pain, implying the activation of ErbB4 in DRG. Using ErbB4-mutant mice, we found reduced pain sensitivity of mice when ErbB4 gene expression was largely ablated; furthermore, ErbB4 deletion decreased the inflammatory pain hypersensitivity of either formalin- or CFA-induced mouse models. Moreover, the pain sensitivity was reduced in mice with specific deletion of ErbB4 on advillin-positive neurons within DRG. Importantly, pain hypersensitivity also decreased in Advillin-Cre;ErbB4-/- cKO mice after formalin- or CFA-induced inflammatory pain. Finally, gene quantification differential expression analysis, using RNAseq technology in combination with GO and KEGG enrichment analysis, suggested that calcium signaling pathway possibly mediated the roles of ErbB4 on DRG sensory neurons in inflammatory pain models. Together, these results indicate that ErbB4 on advillin-positive sensory neurons enhances inflammatory pain sensitivity, providing new clues towards the pathogenic mechanisms of inflammatory pain.

Abstract P004: Targeting the RXR pathway for the prevention of triple-negative breast cancer

Abstract Background: Triple-negative breast cancer (TNBC) is an aggressive cancer that lacks expression of the estrogen receptor (ER), progesterone receptor, and Erb-B2 receptor tyrosine kinase 2. TNBC patients exhibit a poor prognosis, even if treated with chemotherapy. Although studies using selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs) have shown that breast cancer prevention is feasible, these drugs do not prevent ER-negative or TNBC tumors. It has been shown by our laboratory and others that retinoid X receptor (RXR)-specific ligands (rexinoids) can prevent breast cancers that are both ER-positive and ER-negative in mice. In our previous studies in MMTV-erbB2 mice, IRX-4204, a fourth generation rexinoid, prevented the development of most HER2/erbB2-positive tumors in these mice. For this study, we hypothesized that by targeting RXR pathway, we can prevent the development of triple negative, BRCA1-mutant mammary tumors in mice. To test the hypothesis, we treated MMTV-Cre/BRCA1co/co/p53+/- mice prior to their developing tumors with IRX-4204 to determine whether this RXR agonist effectively prevents triple-negative breast tumors. Methods: We tested the tumor preventative effect of IRX-4204 using the established MMTV-Cre/BRCA1co/co/p53+/- mouse model. These mice were produced by breeding MMTV-Cre/BRCA1co/co/p53+/- males and MMTV-Cre/BRCA1co/co/p53+/+ females, and female pups were PCR genotyped. All mice were separated into 4 groups: 1) sesame oil control, 2) IRX-4204 (10 mg/kg), 3) IRX-4204 (20 mg/kg) and 4) 9-cis-UAB-30 (5 mg/kg). All treatments were given by oral gavage, five days a week from 4 months of age. Mice were observed daily for tumor formation and toxicity. The percentage of tumor free mice were recorded, from which tumor incidence and time to tumor formation was visualized using Kaplan Meier curves and analyzed using the Log-rank test. Results: In MMTV-Cre/BRCA1co/co/p53+/- mice, IRX-4204 reduced tumor incidence and was associated with an increase in median tumor free survival time from 209 days to 336 days at 10 mg/kg dose (p=0.005). At the higher dose (20 mg/kg) IRX-4204 also delayed tumor formation with median tumor free survival from 209 days to 260 days (p=0.039). The rexinoid 9-cis-UAB 30 also significantly delayed tumor formation in MMTV-Cre/BRCA1co/co/p53+/- mice with median survival from 209 days to 270 days (p=0.04). Long term treatment of IRX-4204 was not associated with any toxicity. Conclusion: RXR agonist IRX-4204 delayed ER-negative mammary tumor formation in BRCA1co/co; MMTV-Cre; p53+/- mice. Based on our results, IRX-4204 is an effective cancer preventive drug without observed toxicity. Our results suggest that studies with reduced IRX-4204 dose alone or in combination with other targeted therapies such as selective estrogen receptor modulators are warranted. In the future, clinical trials of the IRX-4204 should be considered for the prevention of breast cancer in high-risk patients. (Supported by NCI-PREVENT contract to P. Brown and A. Mazumdar HHSN26100008). Citation Format: Cassandra Moyer, Jamal Hill, Darian Coleman, Shizuko Sei, Altaf Mohammed, Martin Sanders, Powel Brown, Abhijit Mazumdar. Targeting the RXR pathway for the prevention of triple-negative breast cancer. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P004.

MOTS-c and aerobic exercise induce cardiac physiological adaptation via NRG1/ErbB4/CEBPβ modification in rats

AimsTo determine the effects of the mitochondrial open reading frame of the 12S ribosomal RNA type-c (MOTS-c) and aerobic exercise on cardiac structure and function and explore the role of neuregulin-1 (NRG1)- ErbB2 receptor tyrosine kinase 4(ErbB4)- CCAAT-enhancer binding protein β (C/EBPβ) in cardiac physiological adaptation induced by MOTS-c and aerobic training. Main methodsWe used Hematoxylin-Eosin staining(HE)and Transmission Electron Microscope (TEM) to observe the cardiac myocardial structure, carotid artery catheterization to test cardiac function, and real-time quantitative polymerase chain reaction (qRT-PCR) and Western blotting to describe the changes of NRG1, ErbB4, C/EBPβ, and Gata in cardiac physiological adaptation. Key findingsMOTS-c and aerobic training significantly increased heart weight and heart weight index (HWI) (all p < 0.05). Aerobic exercise and MOTS-c treatment thickened myocardial fibers, with a tendency of hypertrophy. Heart rate (HR) (p < 0.001, p = 0.010, p = 0.011), the isovolumic diastolic time constant (Tau) (p < 0.001, p < 0.001, p < 0.001) in exercised (E), MOST-c treated (M) and their combination (ME) decreased significantly, while the dP/dtmax (p < 0.001, p < 0.001, p = 0.039) and dP/dtmin (p < 0.001, p < 0.001, p = 0.001) in groups E, M and ME were significantly higher than those in group C, but EDP (p = 0.903, p = 0.708, p = 0.744) remained unchanged. Moreover, C/EBPβ gene levels were significantly decreased in the differential gene expression between groups C and M transcriptomics sequencing. The levels of ErbB4 mRNA (p < 0.001, p < 0.001, p < 0.001) and Gata4 mRNA (p < 0.001, p < 0.001, p = 0.001) in groups E, M and ME increased significantly, while C/EBPβ mRNA expression decreased significantly (p < 0.001, p = 0.002, p = 0.001), which was consistent with the results of transcriptome sequencing. NRG1 mRNA in group E was significantly higher than that in group C (p = 0.003), but there was no significant difference between groups M and ME (p = 0.804, p = 0.320). The protein expression of NRG1 (p = 0.026, p < 0.001, p < 0.001), ErbB4 (p < 0.001, p < 0.001, p < 0.001) and Gata4 (p = 0.014, p < 0.001, p = 0.006) in groups E, M and ME increased significantly, while C/EBPβ decreased significantly (p < 0.001, p = 0.001, p = 0.002). SignificanceOur findings suggest that MOTS-c and aerobic exercise had similar effects, improving myocardial morphology and structure and enhancing cardiac function through activation of the NRG1-ErbB4-C/EBPβ pathway.

Dysregulation of ErbB4 Signaling Pathway in the Dorsal Hippocampus after Neonatal Hypoxia-Ischemia and Late Deficits in PV+ Interneurons, Synaptic Plasticity and Working Memory

Neonatal hypoxic-ischemic (HI) injury leads to deficits in hippocampal parvalbumin (PV)+ interneurons (INs) and working memory. Therapeutic hypothermia (TH) does not prevent these deficits. ErbB4 supports maturation and maintenance of PV+ IN. Thus, we hypothesized that neonatal HI leads to persistent deficits in PV+ INs, working memory and synaptic plasticity associated with ErbB4 dysregulation despite TH. P10 HI-injured mice were randomized to normothermia (NT, 36 °C) or TH (31 °C) for 4 h and compared to sham. Hippocampi were studied for α-fodrin, glial fibrillary acidic protein (GFAP), and neuroregulin (Nrg) 1 levels; erb-b2 receptor tyrosine kinase 4 (ErbB4)/ Ak strain transforming (Akt) activation; and PV, synaptotagmin (Syt) 2, vesicular-glutamate transporter (VGlut) 2, Nrg1, and ErbB4 expression in coronal sections. Extracellular field potentials and behavioral testing were performed. At P40, deficits in PV+ INs correlated with impaired memory and coincided with blunted long-term depression (LTD), heightened long-term potentiation (LTP) and increased Vglut2/Syt2 ratio, supporting excitatory-inhibitory (E/I) imbalance. Hippocampal Nrg1 levels were increased in the hippocampus 24 h after neonatal HI, delaying the decline documented in shams. Paradoxically ErbB4 activation decreased 24 h and again 30 days after HI. Neonatal HI leads to persistent deficits in hippocampal PV+ INs, memory, and synaptic plasticity. While acute decreased ErbB4 activation supports impaired maturation and survival after HI, late deficit reemergence may impair PV+ INs maintenance after HI.

Erbb4 Deletion From Inhibitory Interneurons Causes Psychosis-Relevant Neuroimaging Phenotypes.

Converging lines of evidence suggest that dysfunction of cortical GABAergic inhibitory interneurons is a core feature of psychosis. This dysfunction is thought to underlie neuroimaging abnormalities commonly found in patients with psychosis, particularly in the hippocampus. These include increases in resting cerebral blood flow (CBF) and glutamatergic metabolite levels, and decreases in ligand binding to GABAA α5 receptors and to the synaptic density marker synaptic vesicle glycoprotein 2A (SV2A). However, direct links between inhibitory interneuron dysfunction and these neuroimaging readouts are yet to be established. Conditional deletion of a schizophrenia susceptibility gene, the tyrosine kinase receptor Erbb4, from cortical and hippocampal inhibitory interneurons leads to synaptic defects, and behavioral and cognitive phenotypes relevant to psychosis in mice. Here, we investigated how this inhibitory interneuron disruption affects hippocampal in vivo neuroimaging readouts. Adult Erbb4 conditional mutant mice (Lhx6-Cre;Erbb4F/F, n = 12) and their wild-type littermates (Erbb4F/F, n = 12) were scanned in a 9.4T magnetic resonance scanner to quantify CBF and glutamatergic metabolite levels (glutamine, glutamate, GABA). Subsequently, we assessed GABAA receptors and SV2A density using quantitative autoradiography. Erbb4 mutant mice showed significantly elevated ventral hippccampus CBF and glutamine levels, and decreased SV2A density across hippocampus sub-regions compared to wild-type littermates. No significant GABAA receptor density differences were identified. These findings demonstrate that specific disruption of cortical inhibitory interneurons in mice recapitulate some of the key neuroimaging findings in patients with psychosis, and link inhibitory interneuron deficits to non-invasive measures of brain function and neurochemistry that can be used across species.

Transcriptomic Changes Associated with ERBB2 Overexpression in Colorectal Cancer Implicate a Potential Role of the Wnt Signaling Pathway in Tumorigenesis

Colorectal cancer (CRC) remains the third most common cause of cancer mortality worldwide. Precision medicine using OMICs guided by transcriptomic profiling has improved disease diagnosis and prognosis by identifying many CRC targets. One such target that has been actively pursued is an erbb2 receptor tyrosine kinase 2 (ERBB2) (Human Epidermal Growth Factor Receptor 2 (HER2)), which is overexpressed in around 3-5% of patients with CRC worldwide. Despite targeted therapies against HER2 showing significant improvement in disease outcomes in multiple clinical trials, to date, no HER2-based treatment has been clinically approved for CRC. In this study we performed whole transcriptome ribonucleic acid (RNA) sequencing on 11 HER2+ and 3 HER2- CRC patients with advanced stages II, III and IV of the disease. In addition, transcriptomic profiling was carried out on CRC cell lines (HCT116 and HT29) and normal colon cell lines (CCD841 and CCD33), ectopically overexpressing ERBB2. Our analysis revealed transcriptomic changes involving many genes in both CRC cell lines overexpressing ERBB2 and in HER2+ patients, compared to normal colon cell lines and HER2- patients, respectively. Gene Set Enrichment Analysis indicated a role for HER2 in regulating CRC pathogenesis, with Wnt/β-catenin signaling being mediated via a HER2-dependent regulatory pathway impacting expression of the homeobox gene NK2 homeobox 5 (NKX2-5). Results from this study thus identified putative targets that are co-expressed with HER2 in CRC warranting further investigation into their role in CRC pathogenesis.

QSAR Study, Molecular Docking, and Pharmacokinetic Analysis of Substituted Dihydropyrimidinone as ErbB2 Inhibitors

ErbB2 is considered to be the preferred dimerization partner among the ErbB receptor tyrosine kinase (RTK) family. They are implicated in the development and progression of several cancer types, majorly breast cancer-related maladies. In the current study, quantitative structure-activity relationship (QSAR), molecular docking approaches and prediction of pharmacokinetic properties were utilized to identify promising ErbB2 inhibitors from a series of dihydropyrimidinone (DHPM) derivatives. The results indicated that the QSAR models of ErbB2 inhibitory activity is robust and has a very good prediction capacity, as exhibited by the value of R which is 0.9194. Furthermore, 6 compounds were shortlisted with potentially high biological activity. These compounds were subjected to drug likeliness, molecular docking and pharmacokinetic evaluations which indicated that the compounds are orally bioavailable and exhibit suitable proficiency as ErbB2 antagonists.

Alterations in prefrontal cortical neuregulin-1 levels in post-pubertal rats with neonatal ventral hippocampal lesions.

Genetic studies in humans have implicated the gene encoding neuregulin-1 (NRG-1) as a candidate susceptibility gene for schizophrenia. Furthermore, it has been suggested that NRG-1 is involved in regulating the expression and function of the N-methyl-D-aspartate receptor and the GABAA receptor in several brain areas, including the prefrontal cortex (PFC), the hippocampus, and the cerebellum. Neonatal ventral hippocampal lesioned (NVHL) rats have been considered as a putative model for schizophrenia with characteristic post-pubertal alteration in response to stress and neuroleptics. In this study, we examined NRG-1, erb-b2 receptor tyrosine kinase 4 (erbB4), and phospho-erbB4 (p-erbB4) levels in the PFC and the distribution of NRG-1 in the NVHL rats by using immunoblotting and immunohistochemical analyses. Neonatal lesions were induced by bilateral injection of ibotenic acid in the ventral hippocampus of postnatal day 7 Sprague-Dawley (SD)-rats. NVHL rats showed significantly decreased levels of NRG-1 and p-erbB4 in the PFC compared to sham controls at post-pubertal period, while the level of erbB4 did not differ between sham and NVHL rats. Moreover, microinjection of NRG-1 into the mPFC improved NVHL-induced prepulse inhibition deficits. Our study suggests PFC NRG-1 alteration as a potential mechanism in schizophrenia-like behaviors in the NVHL model.

NUF2 overexpression contributes to epithelial ovarian cancer progression via ERBB3-mediated PI3K-AKT and MAPK signaling axes.

NDC80 kinetochore complex component (NUF2) is upregulated and plays an important role in various human cancers. However, the function and mechanism of NUF2 in epithelial ovarian cancer (EOC) remain unclear. NUF2 expression was detected in EOC tissues and cell lines. The effects of NUF2 downregulation on cell proliferation, migration and invasion in EOC were analyzed by CCK-8 and Transwell assays. Meanwhile, the effect of NUF2 downregulation on tumor growth in vivo was determined by xenograft tumor models. The mechanisms by which NUF2 regulates EOC progression were detected by RNA sequencing and a series of in vitro assays. We showed that NUF2 was significantly upregulated in EOC tissues and cell lines, and high NUF2 expression was associated with FIGO stage, pathological grade and poor EOC prognosis. NUF2 downregulation decreased cell proliferation, migration, invasion and tumor growth in nude mice. RNA sequencing studies showed that NUF2 knockdown inhibited several genes enriched in the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)-AKT serine/threonine kinase (AKT) and mitogen-activated protein kinase (MAPK) signaling pathways. Erb-B2 receptor tyrosine kinase 3 (ERBB3) was the key factor involved in both of the above pathways. We found that ERBB3 silencing could inhibit EOC progression and repress activation of the PI3K-AKT and MAPK signaling pathways. Furthermore, the exogenous overexpression of ERBB3 partially reversed the inhibitory effects on EOC progression induced by NUF2 downregulation, while LY294002 and PD98059 partially reversed the effects of ERBB3 upregulation. These results showed that NUF2 promotes EOC progression through ERBB3-induced activation of the PI3K-AKT and MAPK signaling axes. These findings suggest that NUF2 might be a potential therapeutic target for EOC.

Cortical wiring by synapse type-specific control of local protein synthesis.

Neurons use local protein synthesis to support their morphological complexity, which requires independent control across multiple subcellular compartments up to the level of individual synapses. We identify a signaling pathway that regulates the local synthesis of proteins required to form excitatory synapses on parvalbumin-expressing (PV+) interneurons in the mouse cerebral cortex. This process involves regulation of the TSC subunit 2 (Tsc2) by the Erb-B2 receptor tyrosine kinase 4 (ErbB4), which enables local control of messenger RNA {mRNA} translation in a cell type-specific and synapse type-specific manner. Ribosome-associated mRNA profiling reveals a molecular program of synaptic proteins downstream of ErbB4 signaling required to form excitatory inputs on PV+ interneurons. Thus, specific connections use local protein synthesis to control synapse formation in the nervous system.

SVCT2–mediated ascorbic acid uptake buffers stress responses via DNA hydroxymethylation reprogramming of S100 calcium-binding protein A4 gene

Vitamin C, a key antioxidant in the central nervous system, cycles between ascorbic acid and dehydroascorbic acid under pathophysiological conditions. Clinical evidence supports that the absence of vitamin C may be linked to depressive symptoms, but much less is known about the mechanism. Herein, we show that chronic stress disrupts the expression of ascorbic acid transporter, sodium-dependent vitamin C transport 2, and induces a deficiency in endogenous ascorbic acid in the medial prefrontal cortex, leading to depressive-like behaviors by disturbing redox-dependent DNA methylation reprogramming. Attractively, ascorbic acid (100 mg/kg-1000 mg/kg, intraperitoneal injection, as bioequivalent of an intravenous drip dose of 0.48 g–4.8 g ascorbic acid per day in humans) produces rapid-acting antidepressant effects via triggering DNA demethylation catalyzed by ten-eleven translocation dioxygenases. In particular, the mechanistic studies by both transcriptome sequencing and methylation sequencing have shown that S100 calcium binding protein A4, a potentially protective factor against oxidative stress and brain injury, mediates the antidepressant activity of ascorbic acid via activating erb-b2 receptor tyrosine kinase 4 (ErbB4)-brain derived neurotrophic factor (BDNF) signaling pathway. Overall, our findings reveal a novel nutritional mechanism that couples stress to aberrant DNA methylation underlying depressive-like behaviors. Therefore, application of vitamin C may be a potential strategy for the treatment of depression.

ODP551 Halting ErbB-2 Isoforms Retrograde Transport to the Nucleus as a New Theragnostic Approach for Triple Negative Breast Cancer

Abstract Triple negative breast cancer (TNBC) is clinically defined by the absence of estrogen and progesterone receptors and the lack of membrane overexpression or gene amplification of the receptor tyrosine kinase ErbB-2/HER2. Due to its heterogeneity, clinical biomarkers and targeted therapies for this disease remain elusive, and chemotherapy has been the standard of care for TNBC. ErbB-2 is classically located at the membrane of BC cells, where it triggers signaling cascades and promotes oncogenesis. We previously demonstrated that ErbB-2 is also localized in the nucleus (NErbB-2) of TNBC cells, from where it drives growth (1). We also discovered that TNBC expresses both wild-type ErbB-2 (WTErbB-2) and alternative ErbB-2 isoform c (ErbB-2c) (1). ErbB-2 migrates to the nucleus via retrograde transport. Here, we revealed that Retro-2, an inhibitor of retrograde transport that protects cells form the deleterious effects of toxins and viruses, evicts both WTErbB-2 and ErbB-2c from the nucleus of BC cells. Using BC models from several molecular subtypes, as well as normal breast cells, we demonstrated that Retro-2 specifically halts the proliferation of cells expressing NErbB-2. Moreover, Retro-2 decreased the expression of genes induced by NErbB-2 (i. e. cyclin D1 and Erk5) and promoted cell cycle arrest at G0/G1 phase and apoptosis. In addition to R2 growth inhibitory activity in vitro, we here also demonstrated that its optimized cyclic derivative Retro-2.1 (in particular the (S)-enantiomer) showed improved efficacy both to evict ErbB-2 isoforms from the nucleus and to inhibit proliferation in vitro. Importantly, Retro-2 eviction of both ErbB-2 isoforms from the nucleus resulted in a striking growth abrogation in multiple TNBC preclinical models, including xenografts and tumor explants). Our mechanistic studies demonstrated that Retro-2 induces a differential accumulation of WTErbB-2 at the early endosomes and plasma membrane, and of ErbB-2c at the Golgi, shedding light both on Retro-2 action on endogenous protein cargoes undergoing retrograde transport and on the biology of ErbB-2 splicing variants. Compelling evidence demonstrated that mRNAs 5' and 3' untranslated regions (UTRs) mediate post-transcriptional regulation of gene expression and determine protein levels and fate. While both T1 and T3 have different 5' but the same 3' UTRs sequences, our in silico studies showed that T1 and T3 RNA secondary structures vary in the region containing both their 5' and 3' UTRs. These findings suggest that T3 secondary structure impacts in its cell specific localization. Together, our present discoveries identify R2 as a precision oncology tool to target NErbB-2 retrograde transport. This novel theragnostic approach could greatly improve the outcome of TNBC patients. (1) Chervo MF et al, Oncogene 2020: 39: 6245-62. Presentation: No date and time listed

Discoidin domain receptor 1 regulates ErbB2/ErbB3 signaling in mammary epithelial cells.

The ErbB2 receptor tyrosine kinase plays a key role in mammary gland development. It forms large clusters which serve as signaling platforms for integration of extracellular information. The discoidin domain receptor (DDR) family are collagen receptor tyrosine kinases which, together with ErbB2, are involved in many physiological and pathological processes. Here, we investigated the interaction of ErbB2 and DDR1 receptors in breast cancer cells. In contrast to beta1-integrin, DDR1 colocalizes with ErbB2 in membrane clusters regardless of their expression levels. We demonstrated that this spatial coexistence is a consequence of the physical interaction between these receptors. In addition, these receptors are coexpressed in the normal mammary gland but not in breast tumor samples. Together, these results present DDR1 as a novel modulator of the ErbB2/ErbB3 signaling pathway.

Emerging Role of ERBB2 in Targeted Therapy for Metastatic Colorectal Cancer: Signaling Pathways to Therapeutic Strategies.

Simple SummaryColorectal cancer (CRC) is the third most commonly diagnosed malignancy and the second most common cause of cancer-related mortality worldwide. Currently available targeted therapies for metastatic CRC mainly target vascular endothelial growth factor and epidermal growth factor receptor in RAS wild-type tumors. Although Erb-B2 receptor tyrosine kinase 2 (ERBB2/human epidermal growth factor receptor 2) plays a significant therapeutic role in breast and gastric cancers, there are no licensed ERBB2-targeted therapies for metastatic CRC. This review aims to outline the molecular biology of ERBB2-positive metastatic CRC and potential targeted therapeutic strategies.Despite recent improvements in the comprehensive therapy of malignancy, metastatic colorectal cancer (mCRC) continues to have a poor prognosis. Notably, 5% of mCRC cases harbor Erb-B2 receptor tyrosine kinase 2 (ERBB2) alterations. ERBB2, commonly referred to as human epidermal growth factor receptor 2, is a member of the human epidermal growth factor receptor family of protein tyrosine kinases. In addition to being a recognized therapeutic target in the treatment of gastric and breast malignancies, it is considered crucial in the management of CRC. In this review, we describe the molecular biology of ERBB2 from the perspective of biomarkers for mCRC-targeted therapy, including receptor structures, signaling pathways, gene alterations, and their detection methods. We also discuss the relationship between ERBB2 aberrations and the underlying mechanisms of resistance to anti-EGFR therapy and immunotherapy tolerance in these patients with a focus on novel targeted therapeutics and ongoing clinical trials. This may aid the development of a new standard of care in patients with ERBB2-positive mCRC.

Genomic characterization reveals distinct mutation landscapes and therapeutic implications in neuroendocrine carcinomas of the gastrointestinal tract.

Neuroendocrine carcinomas of the gastrointestinal tract (GI-NECs) remain a disease of grim prognosis with limited therapeutic options. Their molecular characteristics are still undefined. This study aimed to explore the underlying genetic basis and heterogeneity of GI-NECs. Comprehensive genomic analysis using whole-exome sequencing was performed on 143 formalin-fixed, paraffin-embedded samples of surgically resected GI-NEC with a thorough histological evaluation. Mutational signatures, somatic mutations, and copy number aberrations were analyzed and compared across anatomic locations and histological subtypes. Survival analysis was conducted to identify the independent factors. In total, 143 GI-NECs were examined: the stomach, 87 cases (60.8%); the esophagus, 29 cases (20.3%); the colorectum, 20 cases (14.0%); and the small intestine, 7 cases (4.9%). Eighty-three (58.0%) and 60 (42.0%) cases were subclassified into small cell and large cell subtypes, respectively. GI-NECs showed distinct genetic alterations from their lung counterparts and non-neuroendocrine carcinomas in the same locations. Obvious heterogeneity of mutational signatures, somatic mutations, and copy number variations was revealed across anatomic locations rather than histological subtypes. Except for tumor protein p53 (TP53) and retinoblastoma 1 (RB1), the most frequently mutated genes in the stomach, esophagus, colorectum, and small intestine were low-density lipoprotein receptor-related protein 1B (LRP1B), notch receptor 1 (NOTCH1), adenomatosis polyposis coli (APC), catenin beta 1 (CTNNB1), respectively. Mutations in the WNT-β-catenin, NOTCH and erythroblastic leukemia viral oncogene B (ERBB) pathways were prevalently identified in gastric, esophageal, and colorectal NECs, respectively. Importantly, 104 (72.7%) GI-NECs harbored putative clinically relevant alterations, and non-gastric location and RB1 bi-allelic inactivation with copy number alterations were identified as two independent poor prognostic factors. Furthermore, we found that tumor cells in GI-NECs first gain clonal mutations in TP53, RB1, NOTCH1 and APC, followed by subsequent whole-genome doubling (WGD) and post-WGD clonal mutations in LRP1B, CUB and Sushi multiple domains 3 (CSMD3), FAT tumor suppressor homolog 4 (FAT4) and erb-b2 receptor tyrosine kinase 4 (ERBB4), and finally develop subclonal mutations. GI-NECs harbor distinct genomic landscapes and demonstrate significant genetic heterogeneity across different anatomic locations. Moreover, potentially actionable alterations and prognostic factors were revealed for GI-NECs.

Identification of a Biomarker Combination for Survival Stratification in pStage II/III Gastric Cancer after Curative Resection.

Simple SummaryGastric cancer (GC) is the fifth most common cancer worldwide and the fourth most common cause of cancer-related deaths, with a high frequency of recurrence and metastasis, and a poor prognosis. This study presents a novel combination of four proteins (PDGFRB, INHBA, MMP11, and galectin-10) in GC tissues that have been identified as useful survival stratification markers in patients with pStage II/III GC after curative resection by quantitative polymerase chain reaction (qPCR), proteomic analysis, and immunohistochemistry (IHC).Background: We sought to identify an optimal combination of survival risk stratification markers in patients with pathological (p) stage II/III gastric cancer (GC) after curative resection. Methods: We measured the expression levels of 127 genes in pStage II/III GC tissues of two patient cohorts by quantitative polymerase chain reaction (qPCR) and the expression of 1756 proteins between two prognosis (good and poor) groups by proteomic analysis to identify candidate survival stratification markers. Further, immunohistochemistry (IHC) using tumor microarrays (TMAs) in another cohort of patients was performed to identify an optimal biomarker combination for survival stratification in GC patients. Results: secreted protein acidic and rich in cysteine (SPARC), erb-b2 receptor tyrosine kinase 2 (ERBB2), inhibin subunit beta A (INHBA), matrix metallopeptidase-11 (MMP11), tumor protein p53 (TP53), and platelet-derived growth factor receptor-beta (PDGFRB) were identified as candidate biomarkers from qPCR analysis, and SPARC and galectin-10 were obtained from the proteomic analysis. The combination of PDGFRB, INHBA, MMP11, and galectin-10 was identified as the optimal combination of survival risk stratification markers. Conclusions: A combination of four proteins in GC tissues may serve as useful survival risk stratification markers in patients with pStage II/III GC following curative resection. Our results may facilitate future multicenter prospective clinical trials.

Potential use of lapatinib in the treatment of head and neck squamous cell carcinoma (Review)

To date, cetuximab is the only anti‑epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) approved for the targeted therapy of head and neck squamous cell carcinoma (HNSCC). However, this therapy has left an eloquent number of patients with recurrence and local or/and distance failures, which are associated with Erb‑B2 receptor tyrosine kinase 2 (ERBB2) signaling. The dual targeting (EGFR/ERBB2) irreversible covalent tyrosine kinase inhibitor (TKI), afatinib, has exhibited promising results in HNSCC trials; however, its toxicity arises from further biosynthesis for receptor recovery. Conversely, lapatinib, a reversible TKI, is almost as potent as afatinib, and its interaction with the unique inactive conformation of EGFR has been shown to be associated with its selectivity, specificity and long residence time, resulting in efficacy. However, as a monotherapy, lapatinib appears minimally active and hepatotoxicity has been reported with its use. The present review article summarizes some of the research conducted over the years in order to determine the profile of lapatinib along, with its potential for use in the treatment of HNSCC and associated challenges.

Age-specific impacts of nicotine and withdrawal on hippocampal neuregulin signalling.

Smoking remains the leading cause of preventable death in the United States, with 87% of smokers starting before the age of 18. Age of initiation is a major predictive factor for smoking frequency and successful smoking cessation. People who initiate smoking during adolescences are 2.33 times more likely to become heavy smokers and half as likely to quit compared with smokers who started during adulthood. Additionally, schizophrenia, a disease state linked to altered neurodevelopment during adolescence, is a major predictive factor for smoking status. Smoking rates among people suffering from schizophrenia are between 60% and 90%. Interestingly, the Neuregulin Signalling Pathway (NSP), which plays an important role in neurodevelopment, is implicated in both schizophrenia and nicotine use disorder. Specifically, SNPS in neuregulin 3 (Nrg3) and Erb-B2 Receptor Tyrosine Kinase 4 (ErbB4) have been associated with smoking cessation outcomes and schizophrenia. Here, we examine the effects of chronic nicotine (18 mg/kg/day) and 24-h withdrawal on NSP gene expression in the hippocampus of adult (20-week-old) and adolescent (4-week-old) mice. We show that withdrawal from chronic nicotine decreased the expression of Erbb4 mRNA in the hippocampus of the adult mice but increased the expression of cytosolic Erbb4 protein in adolescent mice. Nrg3 mRNA and protein expression was not altered by chronic nicotine or withdrawal in the adult or adolescent cohorts, but Nrg3 mRNA and synaptosomal protein expression was lower in the adult withdrawal group when compared with their adolescent counterparts. These results highlight the age-specific effects of nicotine withdrawal on the NSP and may contribute to the lower quit rate and higher cigarette consumption of smokers who initiation during adolescences.

ATG12-dependent autophagy is promoted by the erb-b2 receptor tyrosine kinase 2 (ERBB2), contributing to breast cancer cells' resistance to treatment

The erb-b2 receptor tyrosine kinase 2 (ERBB2), a member of the epidermal growth factor receptor (EGFR) family, is overexpressed in a variety of malignancies (radio- and chemotherapy)., While the fundamental processes are yet unknown, treatment resistance does. Autophagy is well-known.to increase resistance to cancer therapy. In this research, we show that ERBB2 rises. Several autophagy genes, such as ATG12 (autophagy-related 12), are expressed, which encouragesautophagy reliant on ATG12. We make it clear that lapatinib, a dual EGFR and ERBB2 inhibitor autophagy was encouraged in cells that only expressed EGFR, but was inhibited in cells that only expressed ERBB2. Furthermore, 35 genes in the canonical autophagy pathway were analyzed from the breast cancer database. Demonstrates that a low relapse-free survival is connected with the overexpression of ATG12 and MAP1LC3B.Likelihood of patients having.

Tumor Characteristics Associated with Lymph Node Metastasis and Prognosis in Patients with ERBB2-Positive Gastric Cancer.

Gastric cancers (GCs) that express human erb-b2 receptor tyrosine kinase 2 (ERBB2, also known as HER2) account for 7.3%-20.2% of GCs. The pathological and prognostic factors associated with lymph node metastasis of such tumors are still unclear. Therefore, we aimed to identify the risk factors for lymph node metastasis and prognostic factors of patients with ERBB2-positive GC. We conducted a retrospective analysis of pathological specimens after D2 radical surgery for locally advanced GC and D1+ surgery performed for early GC in our hospital from January 2015 to December 2018. Patients with ERBB2-positive GC were selected and the potential risk factors for lymph node metastasis and potential factors affecting prognosis were evaluated. Among 1,124 GC patients, 122 diagnosed with ERBB2-positive GC were included in the study. We found that risk factors for lymph node metastasis included tumor size (hazard ratio (HR)- 6.213, 95% confidence interval (CI)- 2.097-18.407, p = 0.001), neural invasion (HR- 2.876, 95% CI - 1.011-8.184, p = 0.048), and vascular invasion (HR- 16.881, 95% CI - 5.207-54.727, p < 0.001). T stage (HR- 4.615, 95% CI - 2.182-9.759, p < 0.001) and vascular invasion (HR- 3.036, 95% CI - 1.369-6.736, p = 0.006) were significant prognostic variables. These findings shed new light on the pathology and prognosis of patients with ERBB2-positive GC.