scholarly journals EGFR/ErbB Inhibition Promotes OPC Maturation up to Axon Engagement by Co-Regulating PIP2 and MBP

Cells ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 844 ◽  
Author(s):  
Emanuela Nocita ◽  
Alice Del Giovane ◽  
Marta Tiberi ◽  
Laura Boccuni ◽  
Denise Fiorelli ◽  
...  
Keyword(s):  
Gene Silencing ◽  
Morphological Changes ◽  
Growth Factor Receptor ◽  
Study Drug ◽  
Drug Efficacy ◽  
Adult Brain ◽  
Egfr Inhibition ◽  
Epidermal Growth ◽  
Oligodendrocyte Precursor ◽  
Neuronal Precursor Cell

Remyelination in the adult brain relies on the reactivation of the Neuronal Precursor Cell (NPC) niche and differentiation into Oligodendrocyte Precursor Cells (OPCs) as well as on OPC maturation into myelinating oligodendrocytes (OLs). These two distinct phases in OL development are defined by transcriptional and morphological changes. How this differentiation program is controlled remains unclear. We used two drugs that stimulate myelin basic protein (MBP) expression (Clobetasol and Gefitinib) alone or combined with epidermal growth factor receptor (EGFR) or Retinoid X Receptor gamma (RXRγ) gene silencing to decode the receptor signaling required for OPC differentiation in myelinating OLs. Electrospun polystyrene (PS) microfibers were used as synthetic axons to study drug efficacy on fiber engagement. We show that EGFR inhibition per se stimulates MBP expression and increases Clobetasol efficacy in OPC differentiation. Consistent with this, Clobetasol and Gefitinib co-treatment, by co-regulating RXRγ, MBP and phosphatidylinositol 4,5-bisphosphate (PIP2) levels, maximizes synthetic axon engagement. Conversely, RXRγ gene silencing reduces the ability of the drugs to promote MBP expression. This work provides a view of how EGFR/ErbB inhibition controls OPC differentiation and indicates the combination of Clobetasol and Gefitinib as a potent remyelination-enhancing treatment.

Recent Advances on Epidermal Growth Factor Receptor as a Molecular Target for Breast Cancer Therapeutics

2020 ◽  
Vol 21 ◽  
Author(s):  
Swathi R. Shetty ◽  
Ragini Yeeravalli ◽  
Tanya Bera ◽  
Amitava Das
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tyrosine Kinase ◽  
Critical Role ◽  
Growth Factor Receptor ◽  
Type I ◽  
Egfr Inhibition ◽  
Epidermal Growth

: Epidermal growth factor receptor (EGFR), a type-I transmembrane protein with intrinsic tyrosine kinase activity is activated by peptide growth factors such as EGF, epigen, amphiregulin, etc. EGFR plays a vital role in regulating cell growth, migration, and differentiation in various tissue-specific cancers. It has been reported to be overexpressed in lung, head, and neck, colon, brain, pancreatic, and breast cancer that trigger tumor progression and drug resistance. EGFR overexpression alters the signaling pathway and induces cell division, invasion, and cell survival. Our prior studies demonstrated that EGFR inhibition modulates chemosensitivity in breast cancer stem cells thereby serving as a potential drug target for breast cancer mitigation. Tyrosine kinase inhibitors (Lapatinib, Neratinib) and monoclonal antibodies (Trastuzumab) targeting EGFR have been developed and approved by the US FDA for clinical use against breast cancer. This review highlights the critical role of EGFR in breast cancer progression and enumerates the various approaches being undertaken to inhibit aggressive breast cancers by suppressing the downstream pathways. Further, the mechanisms of action of potential molecules at various stages of drug development as well as clinically approved drugs for breast cancer treatment are illustrated.

Cutaneous Adverse Effects With HER1/EGFR-Targeted Agents: Is There a Silver Lining?

2005 ◽  
Vol 23 (22) ◽  
pp. 5235-5246 ◽  
Author(s):  
Román Peréz-Soler ◽  
Leonard Saltz
Keyword(s):  
Surrogate Marker ◽  
Growth Factor Receptor ◽  
Dependent Manner ◽  
Activity Data ◽  
Egfr Inhibition ◽  
The Face ◽  
Epidermal Growth ◽  
Management Recommendations ◽  
The Relationship ◽  
Dose Dependent

The human epidermal growth factor receptor (HER1/EGFR) is dysregulated in many solid tumors, making it an attractive target for anticancer therapy. A number of agents that target this receptor are in use or in development. A specific adverse effect common to this class of agent is a papulopustular rash, usually on the face and upper torso, which generally occurs in a dose-dependent manner. Little is known about the etiology of this rash, and there are no clear evidence-based management recommendations. Histologic data indicate that rash may be caused by HER1/EGFR inhibition in skin, although this has not been confirmed. Findings suggest that there is a relationship between the development of rash and response and/or survival, making rash a potential surrogate marker of activity. Data from multiple studies with cetuximab and erlotinib show a consistent relationship between rash and response, as well as between rash and survival. The relationship between rash and clinical outcome is currently less consistent for gefitinib. Some studies report a correlation, whereas others do not. The cause of the possible relationship between rash and clinical benefit remains unclear at this time, and additional studies are needed to determine the clinical utility of this observation.

scholarly journals Efficient Epidermal Growth Factor Receptor Targeting Oligonucleotide as a Potential Molecule for Targeted Cancer Therapy

2019 ◽  
Vol 20 (19) ◽  
pp. 4700 ◽  
Author(s):  
Tao Wang ◽  
Svetlana Philippovich ◽  
Jun Mao ◽  
Rakesh N. Veedu
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Liver Cancer ◽  
Growth Factor Receptor ◽  
Egfr Inhibitors ◽  
Egfr Inhibition ◽  
Wide Range ◽  
Epidermal Growth

Epidermal growth factor receptor (EGFR) is associated with the progression of a wide range of cancers including breast, glioma, lung, and liver cancer. The observation that EGFR inhibition can limit the growth of EGFR positive cancers has led to the development of various EGFR inhibitors including monoclonal antibodies and small-molecule inhibitors. However, the reported toxicity and drug resistance greatly compromised the clinical outcome of such inhibitors. As a type of chemical antibodies, nucleic acid aptamer provides an opportunity to overcome the obstacles faced by current EGFR inhibitors. In this study, we have developed and investigated the therapeutic potential of a 27mer aptamer CL-4RNV616 containing 2′-O-Methyl RNA and DNA nucleotides. Our results showed that CL-4RNV616 not only displayed enhanced stability in human serum, but also effectively recognized and inhibited the proliferation of EGFR positive Huh-7 liver cancer, MDA-MB-231 breast cancer, and U87MG glioblastoma cells, with an IC50 value of 258.9 nM, 413.7 nM, and 567.9 nM, respectively. Furthermore, TUNEL apoptosis assay revealed that CL-4RNV616 efficiently induced apoptosis of cancer cells. In addition, clinical breast cancer biopsy-based immunostaining assay demonstrated that CL-4RNV616 had a comparable detection efficacy for EGFR positive breast cancer with commonly used commercial antibodies. Based on the results, we firmly believe that CL-4RNV616 could be useful in the development of targeted cancer therapeutics and diagnostics.

scholarly journals Dermatologic Toxicities from Monoclonal Antibodies and Tyrosine Kinase Inhibitors against EGFR: Pathophysiology and Management

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Shaad E. Abdullah ◽  
Missak Haigentz ◽  
Bilal Piperdi
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Therapeutic Index ◽  
Egfr Inhibitors ◽  
Egfr Inhibition ◽  
Pancreatic Cancers ◽  
Acneiform Rash ◽  
Dermatological Toxicity ◽  
Epidermal Growth

Epidermal growth factor receptor (EGFR) inhibition has now been well established as an effective treatment for various cancers. The EGFR belongs to the ErbB family of tyrosine kinase receptors which regulate tumor cell differentiation, survival and proliferation. Activation of EGFR drives tumorigenesis in lung, head and neck, colorectal and pancreatic cancers. Irrespective of the type of cancer being treated and the mechanism by which tumor EGFR drives tumorigenesis, the major side effect of EGFR inhibition is a papulopustular (also described as maculopapular or acneiform) rash which occurs in about two thirds of treated patients. Interestingly, this rash has been commonly correlated with better clinical outcomes (objective tumor response and patient survival). The pathophysiology of dermatological toxicity from EGFR inhibitors is an important area of clinical research, and the proper management of the rash is essential to increase the therapeutic index from this class of drugs. In this paper, we review the dermatologic toxicities associated with EGFR inhibitors with an emphasis on its pathophysiology and clinical management.

scholarly journals A two-tiered mechanism of EGFR inhibition by RALT/MIG6 via kinase suppression and receptor degradation

2010 ◽  
Vol 189 (3) ◽  
pp. 557-571 ◽  
Author(s):  
Yuri Frosi ◽  
Sergio Anastasi ◽  
Costanza Ballarò ◽  
Giulia Varsano ◽  
Loriana Castellani ◽  
...  
Keyword(s):  
Cell Transformation ◽  
Growth Factor Receptor ◽  
Kinase Domain ◽  
Egf Receptors ◽  
Genetic Ablation ◽  
Egfr Inhibition ◽  
Catalytic Activation ◽  
Feedback Inhibitor ◽  
Epidermal Growth ◽  
Egfr Kinase

Signaling by epidermal growth factor receptor (EGFR) must be controlled tightly because aberrant EGFR activity may cause cell transformation. Receptor-associated late transducer (RALT) is a feedback inhibitor of EGFR whose genetic ablation in the mouse causes phenotypes due to EGFR-driven excess cell proliferation. RALT inhibits EGFR catalytic activation by docking onto EGFR kinase domain. We report here an additional mechanism of EGFR suppression mediated by RALT, demonstrating that RALT-bound EGF receptors undergo endocytosis and eventual degradation into lysosomes. Moreover, RALT rescues the endocytic deficit of EGFR mutants unable to undergo either endocytosis (Dc214) or degradation (Y1045F) and mediates endocytosis via a domain distinct from that responsible for EGFR catalytic suppression. Consistent with providing a scaffolding function for endocytic proteins, RALT drives EGFR endocytosis by binding to AP-2 and Intersectins. These data suggest a model in which binding of RALT to EGFR integrates suppression of EGFR kinase with receptor endocytosis and degradation, leading to durable repression of EGFR signaling.

scholarly journals Efficacy of EGFR plus TNF inhibition in a preclinical model of temozolomide-resistant glioblastoma

2019 ◽  
Vol 21 (12) ◽  
pp. 1529-1539 ◽  
Author(s):  
Gao Guo ◽  
Ke Gong ◽  
Vineshkumar Thidil Puliyappadamba ◽  
Nishah Panchani ◽  
Edward Pan ◽  
...  
Keyword(s):  
Dna Methyltransferase ◽  
Growth Factor Receptor ◽  
Standard Of Care ◽  
Adult Brain ◽  
Preclinical Model ◽  
Orthotopic Model ◽  
Orthotopic Mouse Model ◽  
Secondary Resistance ◽  
Egfr Inhibition ◽  
Tnf Inhibition

Abstract Background Glioblastoma (GBM) is the most common primary malignant adult brain tumor. Temozolomide (TMZ) is the standard of care and is most effective in GBMs that lack the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). Moreover, even initially responsive tumors develop a secondary resistance to TMZ and become untreatable. Since aberrant epidermal growth factor receptor (EGFR) signaling is widespread in GBM, EGFR inhibition has been tried in multiple clinical trials without success. We recently reported that inhibiting EGFR leads to increased secretion of tumor necrosis factor (TNF) and activation of a survival pathway in GBM. Here, we compare the efficacy of TMZ versus EGFR plus TNF inhibition in an orthotopic mouse model of GBM. Methods We use an orthotopic model to examine the efficacy of TMZ versus EGFR plus TNF inhibition in multiple subsets of GBMs, including MGMT methylated and unmethylated primary GBMs, recurrent GBMs, and GBMs rendered experimentally resistant to TMZ. Results The efficacy of the 2 treatments was similar in MGMT methylated GBMs. However, in MGMT unmethylated GBMs, a combination of EGFR plus TNF inhibition was more effective. We demonstrate that the 2 treatment approaches target distinct and non-overlapping pathways. Thus, importantly, EGFR plus TNF inhibition remains effective in TMZ-resistant recurrent GBMs and in GBMs rendered experimentally resistant to TMZ. Conclusion EGFR inhibition combined with a blunting of the accompanying TNF-driven adaptive response could be a viable therapeutic approach in MGMT unmethylated and recurrent EGFR-expressing GBMs.

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