scholarly journals Physiological functions of keratinocyte epidermal growth factor receptors and their role in the development of skin toxicity during targeted cancer therapy

2021 ◽  
Vol 24 (2) ◽  
pp. 111-118
Author(s):  
Ekaterina V. Orlova
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Egf Receptor ◽  
Growth Factor Receptor ◽  
Pancreatic Head ◽  
Skin Toxicity ◽  
Receptor Activation ◽  
Tyrosine Kinase Receptor ◽  
Long Term Treatment ◽  
Epidermal Growth

The binding of epidermal growth factor (EGFR) receptors is a good target for the treatment of lung, colon, pancreatic, head and neck cancers. The adverse events that develop as a result of therapy, in the form of lesions of the skin and mucous membranes, is a serious problem for the doctor to choose a long-term treatment strategy. The developing symptoms of skin toxicity, as skin problems in patients are often called, are worrisome and often affect the quality of life and compliance with the treatment regimen. Thus, it is important for doctors to know the prerequisites and ways to manage skin toxicity associated with the use of tyrosine kinase receptor inhibitors of epidermal growth factor. The mechanism and consequences of EGF receptor activation are described to explain the development of undesirable skin toxicity associated with inhibition of the epidermal growth factor receptor.

Integrin regulation of epidermal growth factor (EGF) receptor and of EGF-dependent responses

2004 ◽  
Vol 32 (3) ◽  
pp. 438-442 ◽  
Author(s):  
S. Cabodi ◽  
L. Moro ◽  
E. Bergatto ◽  
E. Boeri Erba ◽  
P. Di Stefano ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Egf Receptor ◽  
Growth Factor Receptor ◽  
Transcriptional Response ◽  
Growth Factor Receptors ◽  
Receptor Activation ◽  
Biological Responses ◽  
Epidermal Growth ◽  
And Migration

Integrin signalling co-ordinates with signalling originating from growth factor receptors in the co-operative control of cell proliferation, survival and migration. Increasing evidence suggests that integrins form physical complexes at the cell membrane with growth factor receptors, giving rise to signalling platforms at the adhesive sites. It is probable that at these sites integrins regulate adhesion and at the same time physically constrain and direct the response to soluble growth factors towards proliferation or survival stimuli. These co-operative effects might depend on integrin ability to activate growth factor receptors. In the present paper, we summarize our recent study showing that integrin-dependent adhesion triggers ligand-independent EGFR (epidermal growth factor receptor) activation to transduce downstream signalling. In addition, we also show that integrin-induced signalling pathways are necessary for EGF-dependent transcriptional response, demonstrating the requirement of the co-operation between cell–matrix adhesion and EGFR to achieve full biological responses.

Pharmacogenetic Profiling for Cetuximab Plus Irinotecan Therapy in Patients With Refractory Advanced Colorectal Cancer

2008 ◽  
Vol 26 (9) ◽  
pp. 1427-1434 ◽  
Author(s):  
Francesco Graziano ◽  
Annamaria Ruzzo ◽  
Fotios Loupakis ◽  
Emanuele Canestrari ◽  
Daniele Santini ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Salvage Therapy ◽  
Egf Receptor ◽  
Growth Factor Receptor ◽  
Skin Toxicity ◽  
Egfr Expression ◽  
Intron 1 ◽  
Epidermal Growth

PurposeRegulation of epidermal growth factor receptor (EGFR) signaling pathways may play a relevant role in determining the activity of cetuximab therapy in patients with metastatic colorectal cancer (MCRC). We investigated possible associations between genetic variants and clinical outcomes of MCRC patients treated with cetuximab-irinotecan salvage therapy.Patients and MethodsPatients who underwent cetuximab-irinotecan salvage therapy after disease progression during or after first-line bolus/infusional fluorouracil, leucovorin, and oxaliplatin chemotherapy and a second-line irinotecan-based regimen were considered eligible for analysis of polymorphisms with putative influence on cetuximab-related pathways. Epidermal growth factor (EGF) 61A>G, EGF receptor (EGFR) 216G>T, EGFR 497G>A, EGFR intron-1 (CA)ndinucleotide short (S)/long (L) variant, cyclin-D1 870A>G, immunoglobulin-G fragment-C receptors RIIIa 158G>T, and RIIa 131G>A were studied for a possible association with overall survival (OS) as the primary end point. Additional analyses were addressed at possible associations among polymorphisms and EGFR expression, toxicity, and response.ResultsIn 110 assessable patients, significant association with favorable OS was observed for EGFR intron-1 S/S and EGF 61 G/G genotypes. In the multivariate model, EGFR intron-1 S/S and EGF 61 G/G genotypes showed a hazard ratio of 0.41 (95% CI, 0.21 to 0.78; P = .006) and 0.44 (95% CI, 0.23 to 0.84; P = .01), respectively. EGFR intron-1 S/S carriers showed more frequent G2-G3 skin toxicity (χ2test = 12.7; P = .001) and treatment response (χ2test = 9.45; P = .008) than EGFR intron-1 L/L carriers.ConclusionAlthough additional studies are required for confirmation, our findings could optimize the use of cetuximab in MCRC patients.

scholarly journals Structure-based design of some quinazoline derivatives as epidermal growth factor receptor inhibitors

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Muhammad Tukur Ibrahim ◽  
Adamu Uzairu ◽  
Gideon Adamu Shallangwa ◽  
Sani Uba
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tyrosine Kinase ◽  
Growth Factor Receptor ◽  
Pharmacokinetic Profile ◽  
Egfr Inhibitors ◽  
Tyrosine Kinase Receptor ◽  
Egfr Tyrosine Kinase ◽  
Epidermal Growth

Abstract Background The discovery of epidermal growth factor receptor (EGFR) inhibitors for the treatment of lung cancer, most especially non-small cell lung cancer (NSCLC), was one of the major challenges encountered by the medicinal chemist in the world. The treatment of EGFR tyrosine kinase to manage NSCLCs becomes an urgent therapeutic necessity. NSCLC was the foremost cause of cancer mortality worldwide. Therefore, there is a need to develop more EGFR inhibitors due to the development of drug resistance by the mutation. This research is aimed at designing new EGFR inhibitors using a structure-based design approach. Structure-based drug design comprises several steps such as protein structure retrieval and preparation, ligand library preparation, docking, and structural modification on the best hit compound to design new ones. Result Molecular docking virtual screening on fifty sets of quinazoline derivatives/epidermal growth factor receptor inhibitors against their target protein (EGFR tyrosine kinase receptor PDB entry: 3IKA) and pharmacokinetic profile predictions were performed to identify hit compounds with promising affinities toward their target and good pharmacokinetic profiles. The hit compounds identified were compound 6 with a binding affinity of − 9.3 kcal/mol, compounds 5 and 8, each with a binding affinity of − 9.1 kcal/mol, respectively. The three hit compounds bound to EGFR tyrosine kinase receptor via four different types of interactions which include conventional hydrogen bond, carbon-hydrogen bond, electrostatic, and hydrophobic interactions, respectively. The best hit (compound 6) among the 3 hit compounds was retained as a template and used to design sixteen new EGFR inhibitors. The sixteen newly designed compounds were also docked into the active site of EGFR tyrosine kinase receptor to study their mode of interactions with the receptor. The binding affinities of these newly designed compounds range from − 9.5 kcal/mol to − 10.2 kcal/mol. The pharmacokinetic profile predictions of these newly designed compounds were further examined and found to be orally bioavailable with good absorption, low toxicity level, and permeable properties. Conclusion The sixteen newly designed EGFR inhibitors were found to have better binding affinities than the template used in the designing process and afatinib the positive control (an FDA approved EGFR inhibitor). None of these designed compounds was found to violate more than the permissible limit set by RO5. More so, the newly designed compounds were found to have good synthetic accessibility which indicates that these newly designed compounds can be easily synthesized in the laboratory.

scholarly journals Epidermal Growth Factor Receptor Inhibitors: A Review of Cutaneous Adverse Events and Management

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
K. Chanprapaph ◽  
V. Vachiramon ◽  
P. Rattanakaemakorn
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Adverse Events ◽  
Current Knowledge ◽  
Growth Factor Receptor ◽  
Skin Toxicity ◽  
Maculopapular Rash ◽  
Postinflammatory Hyperpigmentation ◽  
Epidermal Growth

Epidermal growth factor inhibitors (EGFRI), the first targeted cancer therapy, are currently an essential treatment for many advance-stage epithelial cancers. These agents have the superior ability to target cancers cells and better safety profile compared to conventional chemotherapies. However, cutaneous adverse events are common due to the interference of epidermal growth factor receptor (EGFR) signaling in the skin. Cutaneous toxicities lead to poor compliance, drug cessation, and psychosocial discomfort. This paper summarizes the current knowledge concerning the presentation and management of skin toxicity from EGFRI. The common dermatologic adverse events are papulopustules and xerosis. Less common findings are paronychia, regulatory abnormalities of hair growth, maculopapular rash, mucositis, and postinflammatory hyperpigmentation. Radiation enhances EGFRI rash due to synergistic toxicity. There is a positive correlation between the occurrence and severity of cutaneous adverse effects and tumor response. To date, prophylactic systemic tetracycline and tetracycline class antibiotics have proven to be the most effective treatment regime.

scholarly journals Epidermal Growth Factor Receptor Distribution during Chemotactic Responses

2000 ◽  
Vol 11 (11) ◽  
pp. 3873-3883 ◽  
Author(s):  
Maryse Bailly ◽  
Jeffrey Wyckoff ◽  
Boumediene Bouzahzah ◽  
Ross Hammerman ◽  
Vonetta Sylvestre ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Egf Receptor ◽  
Fluorescent Protein ◽  
Growth Factor Receptor ◽  
Spatial Gradient ◽  
Spatial Gradients ◽  
Epidermal Growth ◽  
Green Fluorescent

To determine the distribution of the epidermal growth factor (EGF) receptor (EGFR) on the surface of cells responding to EGF as a chemoattractant, an EGFR-green fluorescent protein chimera was expressed in the MTLn3 mammary carcinoma cell line. The chimera was functional and easily visualized on the cell surface. In contrast to other studies indicating that the EGFR might be localized to certain regions of the plasma membrane, we found that the chimera is homogeneously distributed on the plasma membrane and becomes most concentrated in vesicles after endocytosis. In spatial gradients of EGF, endocytosed receptor accumulates on the upgradient side of the cell. Visualization of the binding of fluorescent EGF to cells reveals that the affinity properties of the receptor, together with its expression level on cells, can provide an initial amplification step in spatial gradient sensing.

Involvement of Shc in insulin- and epidermal growth factor-induced activation of p21ras

1994 ◽  
Vol 14 (3) ◽  
pp. 1575-1581
Author(s):  
G J Pronk ◽  
A M de Vries-Smits ◽  
L Buday ◽  
J Downward ◽  
J A Maassen ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Insulin Receptor ◽  
Tyrosine Phosphorylation ◽  
Egf Receptor ◽  
Growth Factor Receptor ◽  
Nucleotide Exchange ◽  
Similar Time ◽  
Epidermal Growth

Shc proteins are phosphorylated on tyrosine residues and associate with growth factor receptor-bound protein 2 (Grb2) upon treatment of cells with epidermal growth factor (EGF) or insulin. We have studied the role of Shc in insulin- and EGF-induced activation of p21ras in NIH 3T3 cells overexpressing human insulin receptors (A14 cells). A14 cells are equally responsive to insulin and EGF with respect to activation of p21ras. Analysis of Shc immunoprecipitates revealed that (i) both insulin and EGF treatment resulted in Shc tyrosine phosphorylation and (ii) Shc antibodies coimmunoprecipitated both Grb2 and mSOS after insulin and EGF treatment. The induction of tyrosine phosphorylation of Shc and the presence of Grb2 and mSOS in Shc immunoprecipitates followed similar time courses, with somewhat higher levels after EGF treatment. In mSOS immunoprecipitates, Shc could be detected as well. Furthermore, Shc immune complexes contained guanine nucleotide exchange activity toward p21ras in vitro. From these results, we conclude that after insulin and EGF treatment, Shc associates with both Grb2 and mSOS and therefore may mediate, at least in part, insulin- and EGF-induced activation of p21ras. In addition, we investigated whether the Grb2-mSOS complex associates with the insulin receptor or with insulin receptor substrate 1 (IRS1). Although we observed association of Grb2 with IRS1, we did not detect complex formation between mSOS and IRS1 in experiments in which the association of mSOS with Shc was readily detectable. Furthermore, whereas EGF treatment resulted in the association of mSOS with the EGF receptor, insulin treatment did not result in the association of mSOS with the insulin receptor. These results indicate that the association of Grb2-nSOS with Shc may be an important event in insulin-induced, mSOS-mediated activation of p21ras.

An epidermal growth factor receptor/ret chimera generates mitogenic and transforming signals: evidence for a ret-specific signaling pathway

1994 ◽  
Vol 14 (1) ◽  
pp. 663-675
Author(s):  
M Santoro ◽  
W T Wong ◽  
P Aroca ◽  
E Santos ◽  
B Matoskova ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tyrosine Kinases ◽  
Mammalian Cells ◽  
Egf Receptor ◽  
Biological Effects ◽  
Ectopic Expression ◽  
Growth Factor Receptor ◽  
Dependent Signal ◽  
Epidermal Growth

A chimeric expression vector which encoded for a molecule encompassing the extracellular domain of the epidermal growth factor (EGF) receptor (EGFR) and the intracellular domain of the ret kinase (EGFR/ret chimera) was generated. Upon ectopic expression in mammalian cells, the EGFR/ret chimera was correctly synthesized and transported to the cell surface, where it was shown capable of binding EGF and transducing an EGF-dependent signal intracellularly. Thus, the EGFR/ret chimera allows us to study the biological effects and biochemical activities of the ret kinase under controlled conditions of activation. Comparative analysis of the growth-promoting activity of the EGFR/ret chimera expressed in fibroblastic or hematopoietic cells revealed a biological phenotype clearly distinguishable from that of the EGFR, indicating that the two kinases couple with mitogenic pathways which are different to some extent. Analysis of biochemical pathways implicated in the transduction of mitogenic signals also evidenced significant differences between the ret kinase and other receptor tyrosine kinases. Thus, the sum of our results indicates the existence of a ret-specific pathway of mitogenic signaling.

Antibiotics in prevention of skin toxic reactions of epidermal growth factor receptor inhibitors (literature review)

2021 ◽  
pp. 8-11
Author(s):  
L. S. Kruglova ◽  
I. A. Koroleva
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Topical Therapy ◽  
Growth Factor Receptor ◽  
Skin Toxicity ◽  
Egfr Inhibitors ◽  
Tetracycline Antibiotics ◽  
Negative Effect ◽  
Epidermal Growth

The article is an overview and contains up-to-date information on the use of tetracycline antibiotics in the prevention of acne-like rash in patients receiving therapy with epidermal growth factor receptor inhibitors. According to studies, prevention of skin toxicity is necessary to maintain the effectiveness of the antitumor effect of EGFR inhibitors and to minimize the negative effect of adverse effects from the skin on the quality of life of patients. The use of tetracycline antibiotics in combination with topical therapy and photoprotection for the prevention of acne-like rash against the background of the use of EGFR inhibitors is a fairly safe method for long-term use. Of the antibacterial drugs for the prevention of acne-like rash, the most advisable is the appointment of doxycycline at a dose of 100 mg per day from the first day of taking EGFR inhibitors.

scholarly journals Asbestos-induced phosphorylation of epidermal growth factor receptor is linked to c-fos and apoptosis

1999 ◽  
Vol 277 (4) ◽  
pp. L684-L693 ◽  
Author(s):  
Christine L. Zanella ◽  
Cynthia R. Timblin ◽  
Andrew Cummins ◽  
Michael Jung ◽  
Jonathan Goldberg ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Egf Receptor ◽  
Growth Factor Receptor ◽  
Direct Interaction ◽  
Mrna Levels ◽  
Binding Studies ◽  
Therapeutic Implications ◽  
Asbestos Fibers ◽  
Epidermal Growth

We examined the mechanisms of interaction of crocidolite asbestos fibers with the epidermal growth factor (EGF) receptor (EGFR) and the role of the EGFR-extracellular signal-regulated kinase (ERK) signaling pathway in early-response protooncogene (c- fos/c- jun) expression and apoptosis induced by asbestos in rat pleural mesothelial (RPM) cells. Asbestos fibers, but not the nonfibrous analog riebeckite, abolished binding of EGF to the EGFR. This was not due to a direct interaction of fibers with ligand, inasmuch as binding studies using fibers and EGF in the absence of membranes showed that EGF did not adsorb to the surface of asbestos fibers. Exposure of RPM cells to asbestos caused a greater than twofold increase in steady-state message and protein levels of EGFR ( P < 0.05). The tyrphostin AG-1478, which inhibits the tyrosine kinase activity of the EGFR, but not the tyrphostin A-10, which does not affect EGFR activity, significantly ameliorated asbestos-induced increases in mRNA levels of c- fos but not of c- jun. Pretreatment of RPM cells with AG-1478 significantly reduced apoptosis in cells exposed to asbestos. Our findings suggest that asbestos-induced binding to EGFR initiates signaling pathways responsible for increased expression of the protooncogene c- fos and the development of apoptosis. The ability to block asbestos-induced elevations in c- fos mRNA levels and apoptosis by small-molecule inhibitors of EGFR phosphorylation may have therapeutic implications in asbestos-related diseases.

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