Epidermal growth factor receptor: Structure-function informing the design of anticancer therapeutics

Mitchell, Ruth A.; Luwor, Rodney B; Burgess, AW

doi:10.1016/j.yexcr.2018.08.009

Cited by 72 publications

(49 citation statements)

References 263 publications

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“…The ligand-binding leads to conformational changes in the kinase structure and activates the ATP site for auto-phosphorylation. Once the phosphorylation starts, the C-lobe shrinks towards the N-lobe and the kinase receptor are activated [37]. The ATP site is a highly reactive and unstable site due to continuous auto-phosphorylation (Fig.…”

Section: Role Of Egfr In Nsclc and Gatekeeper Mutationsmentioning

confidence: 99%

Advances in targeting EGFR allosteric site as anti-NSCLC therapy to overcome the drug resistance

2020

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Background The epidermal growth factor receptor (EGFR) inhibitors represent the first-line therapy regimen for non-small cell lung cancer (NSCLC). Most of these inhibitors target the ATP-site to stop the aggressive development of NSCLC. Stabilization of the ATP-binding on EGFR is difficult due to autophosphorylation of the EGFR domain. This leads to activation of nonintrinsic influence of the tumor microenvironment and expression of anti-apoptotic pathways and drug resistance. Methods The NSCLC related literature search was carried out using online databases such as Scopus, Web of Sciences, PubMed, Protein Data Bank and UniPort for the last ten years and selected articles are referred for discussion in this review. Results To overcome the problem of mutations in NSCLC, the allosteric site of EGFR was targeted, which shows significant therapeutic outcome without causing resistance. Compounds like EAI001, EAI045 JBJ-04-125-02, DDC4002 and a series of small molecules with an affinity towards the EGFR allosteric site are reported and are under the investigational stage. These compounds are categorized under fourth-generation anti-NSCLC agents. Conclusion Composition of this review highlights the advantage of inhibiting allosteric site in the EGFRTK receptor domains and presents a comparative analysis of the new fourth-generation anti-NSCLC agents to overcome the drug resistance.

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Section: Role Of Egfr In Nsclc and Gatekeeper Mutationsmentioning

confidence: 99%

Advances in targeting EGFR allosteric site as anti-NSCLC therapy to overcome the drug resistance

2020

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“…Multiple types of cancer have been found to exhibit over expression of EGFR, making it a candidate for targeted therapy. Current therapeutic interventions specific to EGFR include treatment of lung, pancreatic, and colorectal cancers, among others [152][153][154][155].…”

Section: Epidermal Growth Factor Receptormentioning

confidence: 99%

Current Targets and Bioconjugation Strategies in Photodynamic Diagnosis and Therapy of Cancer

Gómez

Tsung

2020

Molecules

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Photodynamic diagnosis (PDD) and therapy (PDT) are emerging, non/minimally invasive techniques for cancer diagnosis and treatment. Both techniques require a photosensitizer and light to visualize or destroy cancer cells. However, a limitation of conventional, non-targeted PDT is poor selectivity, causing side effects. The bioconjugation of a photosensitizer to a tumor-targeting molecule, such as an antibody or a ligand peptide, is a way to improve selectivity. The bioconjugation strategy can generate a tumor-targeting photosensitizer conjugate specific for cancer cells, or ideally, for multiple tumor compartments to improve selectivity and efficacy, such as cancer stem cells and tumor neovasculature within the tumor microenvironment. If successful, such targeted photosensitizer conjugates can also be used for specific visualization and detection of cancer cells and/or tumor angiogenesis (an early event in tumorigenesis) with the hope of an early diagnosis of cancer. The purpose of this review is to summarize some current promising target molecules, e.g., tissue factor (also known as CD142), and the currently used bioconjugation strategies in PDT and PDD, with a focus on newly developed protein photosensitizers. These are genetically engineered photosensitizers, with the possibility of generating a fusion protein photosensitizer by recombinant DNA technology for both PDT and PDD without the need of chemical conjugation. We believe that providing an overview of promising targets and bioconjugation strategies will aid in driving research in this field forward towards more effective, less toxic, and non- or minimally invasive treatment and diagnosis options for cancer patients.

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“…Signaling from the receptors of the EGF family is regulated by a set of ligands (EGF-like ligands). To date, seven EGF-like ligands have been described, which can be categorized as high-affinity ligands of EGFR (transforming growth factor-alpha (TGF-α), betacellulin (BTC), epidermal growth factor (EGF), and heparin-binding growth factor (HB-EGF)) and low-affinity ligands of EGFR (epiregulin (EREG), amphiregulin (AREG), and epigen (EPGN)) [29,30]. These ligands form homo- or heterodimerization with the receptors of the EGFR family for receptor activation, thereby stimulating the intracellular domain with tyrosine kinase signaling to activate the signaling cascade.…”

Section: Epidermal Growth Factor Receptor Family and Their Ligandsmentioning

confidence: 99%

Advances in Targeting the Epidermal Growth Factor Receptor Pathway by Synthetic Products and Its Regulation by Epigenetic Modulators as a Therapy for Glioblastoma

Abbas

Kausar

Wang

et al. 2019

Cells

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Glioma is the most common primary tumor of the nervous system, and approximately 50% of patients exhibit the most aggressive form of the cancer, glioblastoma. The biological function of epidermal growth factor receptor (EGFR) in tumorigenesis and progression has been established in various types of cancers, since it is overexpressed, mutated, or dysregulated. Its overexpression has been shown to be associated with enhanced metastatic potential in glioblastoma, with EGFR at the top of a downstream signaling cascade that controls basic functional properties of glioblastoma cells such as survival, cell proliferation, and migration. Thus, EGFR is considered as an important therapeutic target in glioblastoma. Many anti-EGFR therapies have been investigated both in vivo and in vitro, making their way to clinical studies. However, in clinical trials, the potential efficacy of anti-EGFR therapies is low, primarily because of chemoresistance. Currently, a range of epigenetic drugs including histone deacetylase (HDAC) inhibitors, DNA methylation and histone inhibitors, microRNA, and different types of EGFR inhibitor molecules are being actively investigated in glioblastoma patients as therapeutic strategies. Here, we describe recent knowledge on the signaling pathways mediated by EGFR/EGFR variant III (EGFRvIII) with regard to current therapeutic strategies to target EGFR/EGFRvIII amplified glioblastoma.

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Epidermal growth factor receptor: Structure-function informing the design of anticancer therapeutics

Cited by 72 publications

References 263 publications

Advances in targeting EGFR allosteric site as anti-NSCLC therapy to overcome the drug resistance

Advances in targeting EGFR allosteric site as anti-NSCLC therapy to overcome the drug resistance

Current Targets and Bioconjugation Strategies in Photodynamic Diagnosis and Therapy of Cancer

Advances in Targeting the Epidermal Growth Factor Receptor Pathway by Synthetic Products and Its Regulation by Epigenetic Modulators as a Therapy for Glioblastoma

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