Structural pharmacological studies on EGFR T790M/C797S

Kong, Lulu; Ma, Rui; Yao, Ming-Yu; Yan, Xiao-E; Zhu, Sujie; Zhao, Peng; Yun, Cai‐Hong

doi:10.1016/j.bbrc.2017.04.138

Cited by 34 publications

(26 citation statements)

References 31 publications

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“…The influence of mutations and similarities in pharmacological properties was also observed in different families ( Figure 1 , Figure 2 ). X-ray crystallography showed that the ATP-binding cleft between the N-lobe and C-lobe can be wider or narrower as a result of different crystal packing [26] , which we assume can influence the flexibility of the glycine-rich P-loop. Our comparative analysis shows highly distinct conformational landscapes for each of the mutant combinations.…”

Section: Comparative Overview Of Egfr Crystal Structuresmentioning

confidence: 87%

Toward structure-based drug design against the epidermal growth factor receptor (EGFR)

Haddad

Remeš

Adam

et al. 2021

Drug Discovery Today

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Highlights Structural variations in EGFR should not be ignored in structure-based drug design. Main variations involve inward and outward folding of C-helix in the kinase N-lobe. Origins of variations are mutations and drug R-groups but not the drug core. Comparative modeling, fitting and clustering are imperative steps in EGFR drug design. Alternatively, volume and shape of binding site can be used to filter ligands against structures.

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Section: Comparative Overview Of Egfr Crystal Structuresmentioning

confidence: 87%

Toward structure-based drug design against the epidermal growth factor receptor (EGFR)

Haddad

Remeš

Adam

et al. 2021

Drug Discovery Today

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“… 25 Structural studies with compound Go6976, a potent protein kinase C (PKC) inhibitor that also binds preferentially to EGFR T790M, bound to EGFR T790M/C797S support the idea that non-ATP competitive inhibitors may be preferential to overcome the presence of C797S. 26 Whether a similar strategy is applicable to the G796S solvent-front alteration observed in our patient is unstudied. Overall, the optimal approach to EGFR tertiary mutation positive (EGFRm3+) tumors remains an unknown, and we anticipate combination approaches will be needed.…”

Section: Discussionmentioning

confidence: 71%

<em>Cis</em>-oriented solvent-front EGFR G796S mutation in tissue and ctDNA in a patient progressing on osimertinib: a case report and review of the literature

Klempner¹,

Mehta²,

Schrock³

et al. 2017

LCTT

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Acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) is a universal event and limits clinical efficacy. The third-generation EGFR inhibitor osimertinib is active in EGFR-mutant/T790M positive non-small-cell lung cancer. Mechanisms of acquired resistance are emerging, and here we describe a cis-oriented solvent-front EGFR G796S mutation as the resistance mechanism observed in a progression biopsy and circulating tumor DNA (ctDNA) from a patient with initial response followed by progression on osimertinib. This is one of the earliest reports of a sole solvent-front tertiary EGFR mutation as a resistance mechanism to osimertinib. Our case suggests a monoclonal resistance mechanism. We review the importance of the solvent-front residues across TKIs and describe known osimertinib resistance mechanisms. We observe that nearly all clinical osimertinib-resistant tertiary EGFR mutations are oriented in cis with EGFR T790M. This case highlights the importance of mutations affecting EGFR kinase domains and supports the feasibility of broad panel ctDNA assays for detection of novel acquired resistance and tumor heterogeneity in routine clinical care.

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“…First, we presume that the observed cysteine oxidations in our studies apply primarily to C797 within the ATP-binding region of the EGFR kinase domain 26,37 . Indeed, C797 sulfenylation may affect kinase function, but C797 is not essential for EGFR kinase activity 26,57 . Also, C797 is a target for covalent EGFR kinase inhibitors and the use of third-generation EGFR-TKI such as AZD9291 has led to novel acquired resistance mechanisms including a newly acquired cysteine to serine mutation (C797S) 13,15 .…”

Section: Discussionmentioning

confidence: 99%

Dysregulated Redox Regulation Contributes to Nuclear EGFR Localization and Pathogenicity in Lung Cancer

Little

Hristova

Lith

et al. 2019

Sci Rep

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Lung cancers are frequently characterized by inappropriate activation of epidermal growth factor receptor (EGFR)-dependent signaling and epigenetic silencing of the NADPH oxidase (NOX) enzyme DUOX1, both potentially contributing to worse prognosis. Based on previous findings linking DUOX1 with redox-dependent EGFR activation, the present studies were designed to evaluate whether DUOX1 silencing in lung cancers may be responsible for altered EGFR regulation. In contrast to normal epithelial cells, EGF stimulation of lung cancer cell lines that lack DUOX1 promotes EGF-induced EGFR internalization and nuclear localization, associated with induction of EGFR-regulated genes and related tumorigenic outcomes. Each of these outcomes could be reversed by overexpression of DUOX1 or enhanced by shRNA-dependent DUOX1 silencing. EGF-induced nuclear EGFR localization in DUOX1-deficient lung cancer cells was associated with altered dynamics of cysteine oxidation of EGFR, and an overall reduction of EGFR cysteines. These various outcomes could also be attenuated by silencing of glutathione S-transferase P1 (GSTP1), a mediator of metabolic alterations and drug resistance in various cancers, and a regulator of cysteine oxidation. Collectively, our findings indicate DUOX1 deficiency in lung cancers promotes dysregulated EGFR signaling and enhanced GSTP1-mediated turnover of EGFR cysteine oxidation, which result in enhanced nuclear EGFR localization and tumorigenic properties.

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Structural pharmacological studies on EGFR T790M/C797S

Cited by 34 publications

References 31 publications

Toward structure-based drug design against the epidermal growth factor receptor (EGFR)

Toward structure-based drug design against the epidermal growth factor receptor (EGFR)

<em>Cis</em>-oriented solvent-front EGFR G796S mutation in tissue and ctDNA in a patient progressing on osimertinib: a case report and review of the literature

Dysregulated Redox Regulation Contributes to Nuclear EGFR Localization and Pathogenicity in Lung Cancer

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