A cell-based drug discovery assay identifies inhibition of cell stress responses as a new approach to treatment of epidermolysis bullosa simplex

ABSTRACT In the skin fragility disorder epidermolysis bullosa simplex (EBS), mutations in keratin 14 (K14, also known as KRT14) or keratin 5 (K5, also known as KRT5) lead to keratinocyte rupture and skin blistering. Severe forms of EBS are associated with cytoplasmic protein aggregates, with elevated kinase activation of ERK1 and ERK2 (ERK1/2; also known as MAPK3 and MAPK1, respectively), suggesting intrinsic stress caused by misfolded keratin protein. Human keratinocyte EBS reporter cells stably expressing GFP-tagged EBS-mimetic mutant K14 were used to optimize a semi-automated system to quantify the effects of test compounds on keratin aggregates. Screening of a protein kinase inhibitor library identified several candidates that reduced aggregates and impacted on epidermal growth factor receptor (EGFR) signalling. EGF ligand exposure induced keratin aggregates in EBS reporter keratinocytes, which was reversible by EGFR inhibition. EBS keratinocytes treated with a known EGFR inhibitor, afatinib, were driven out of activation and towards quiescence with minimal cell death. Aggregate reduction was accompanied by denser keratin filament networks with enhanced intercellular cohesion and resilience, which when extrapolated to a whole tissue context would predict reduced epidermal fragility in EBS patients. This assay system provides a powerful tool for discovery and development of new pathway intervention therapeutic avenues for EBS.

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Effect of additional inhibition of human epidermal growth factor receptor 2 with the bispecific tyrosine kinase inhibitor AEE788 on the resistance to specific EGFR inhibition in glioma cells

International Journal of Molecular Medicine ◽

10.3892/ijmm_00000518 ◽

2010 ◽

Vol 26 (5) ◽

Cited By ~ 5

Author(s):

Berezowska

Keyword(s):

Epidermal Growth Factor Receptor ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitor ◽

Kinase Inhibitor ◽

Growth Factor Receptor ◽

Glioma Cells ◽

Egfr Inhibition ◽

Epidermal Growth

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EGFR inhibition for metastasized cutaneous squamous cell carcinoma in dystrophic epidermolysis bullosa

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-019-1262-7 ◽

2019 ◽

Vol 14 (1) ◽

Cited By ~ 4

Author(s):

Andrea Diociaiuti ◽

Holger Steinke ◽

Alexander Nyström ◽

Agnes Schwieger-Briel ◽

Frank Meiss ◽

...

Keyword(s):

Squamous Cell ◽

Epidermolysis Bullosa ◽

Locally Advanced ◽

Growth Factor Receptor ◽

Cancer Treatments ◽

Dystrophic Epidermolysis Bullosa ◽

Egfr Inhibition ◽

Therapeutic Decisions ◽

Skin Fragility ◽

Epidermal Growth

AbstractDystrophic epidermolysis bullosa (DEB) is a hereditary skin fragility disorder, characterized by trauma-induced blistering followed by soft tissue fibrosis. One of the most feared complications is the early development of aggressive cutaneous squamous cell carcinomas (SCC). For patients with locally advanced or metastasized SCCs treatment with cetuximab, a monoclonal antibody against epidermal growth factor receptor (EGFR), has been proposed and so far, treatment of five DEB patients with cetuximab has been published. With this report, we extend the spectrum of EB patients treated with cetuximab by adding two additional patients. Taking together all DEB cases treated with cetuximab, we propose that cetuximab should be administered as early as possible, since it seems to be more efficient and is accompanied by rather mild adverse effects. We also show that EGFR is frequently expressed in DEB-associated SCCs, although there were noticeable differences in the level of expression, which may influence responsiveness to EGFR-targeting therapies. Although only limited experiences with targeted cancer treatments in EB exist, such reports highlight the treatments’ effects in this specific cohort and assist our therapeutic decisions.

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Case Report: EGFR-Positive Early-Stage Lung Adenocarcinoma Transforming to Squamous Cell Carcinoma After TKI Treatment

Frontiers in Oncology ◽

10.3389/fonc.2021.696881 ◽

2021 ◽

Vol 11 ◽

Author(s):

Jiatao Liao ◽

Yuan Li ◽

Chang Liu ◽

Qianqian Long ◽

Jialei Wang

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Kinase Inhibitor ◽

Early Stage ◽

Growth Factor Receptor ◽

Squamous Differentiation ◽

Egfr Inhibition ◽

Histological Transformation ◽

Tki Treatment

The histological transformation from epidermal growth factor receptor (EGFR)-mutated adenocarcinoma (ADC) to squamous cell carcinoma (SCC) after tyrosine kinase inhibitor (TKI) treatment is rare. We present a case of a patient who transitioned from early-stage primary lung ADC with partial squamous differentiation, EGFR mutation and amplification, to adrenal gland metastasis as SCC with EGFR amplification disappearance 115-months after surgery, during which gefitinib and local radiotherapy were utilized for the metastasis in the right femoral head and mediastinal lymph nodes. This case might indicate a possible mechanism of EGFR inhibition resistance with SCC transition and EGFR amplification loss from the initially well-responding ADC, especially those with SCC or partial squamous differentiation. The optimal post-progression therapy for ADC-SCC patients is challenging and further studies are needed.

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