The Combi-Targeting concept postulates that a molecule termed combi-molecule (C-molecule) with binary epidermal growth factor receptor (EGFR) targeting/DNA-damaging properties and with the ability to be hydrolyzed to another EGFR inhibitor should induce sustained antiproliferative activity in cells overexpressing EGFR. Because we postulate that the EGFR affinity of the C-molecule and that of its hydrolytic metabolites are critical parameters for sustained potency against EGFR-overexpressing cells, we synthesized BJ2000 (IC(50) = 0.1 microM, competitive binding at ATP site), a novel C-molecule that can decompose into a 6-amino-4-anilinoquinazoline FD105 (IC(50) = 0.2 microM). Studies using the EGFR-overexpressing A431 cells revealed that BJ2000 could damage DNA and block epidermal growth factor-stimulated EGFR autophosphorylation by a partially irreversible mechanism. Blockade of EGFR autophosphorylation subsequently induced inhibition of mitogen-activated protein kinase activation and c-fos gene expression. Enzyme-linked immunosorbent assay and growth factor-mediated stimulation of proliferation assays in the EGFR-expressing NIH3T3HER14 demonstrated the preferential EGFR-targeting properties of BJ2000, and more importantly suggest that blockade of EGFR phosphorylation by this drug translate into significant growth inhibitory effects. These properties culminated into irreversible antiproliferative effects as confirmed by a sulforhodamine B assay. Five days after a 2-h treatment, BJ2000 retained significant antiproliferative effect in A431 cells, whereas its reversible metabolite FD105 almost completely lost its activity. This result in toto lend support to the Combi-Targeting concept according to which a molecular conjugate kept small enough to interact with EGFR and designed to degrade into another inhibitor of the same target plus a DNA-damaging species may induce sustained growth inhibitory effect in EGFR-overexpressing cells.
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http://dx.doi.org/10.1124/jpet.102.039099 | DOI Listing |
Breast Cancer (Dove Med Press)
January 2025
Department of Medical Oncology, Chinese PLA General Hospital, Beijing, 100853, People's Republic of China.
Purpose: This study aims to explore the role of the non-luminal disease score (NOLUS) for everolimus in patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC).
Methods: NOLUS has previously been established as an algorithm: NOLUS (0-100) = - 0.45 × ER(%) - 0.
Postepy Dermatol Alergol
December 2024
Department of Dermatology, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
Introduction: Systemic sclerosis is a complex disease characterized by the fibrosis and vasculopathy.
Aim: We aimed to assess scleroderma by examining involucrin, an early terminal differentiation marker of epidermal keratinocytes.
Material And Methods: Immunolocalization of involucrin was performed in healthy controls and patients with scleroderma lesions by using an immunofluorescence (IF) assay.
Acta Oncol
January 2025
Department of Surgical Pathology, Zealand University Hospital, Roskilde, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
Background And Purpose: Despite advancements in genetic testing and expanded eligibility criteria, underutilisation of germline testing for pathogenic variants in BRCA1 and BRCA2 (BRCA) remains evident among breast cancer (BC) patients. This observational cohort study presents real-world data on BRCA testing within the context of clinical practice challenges, including incomplete family history and under-referral.
Material And Methods: From the Danish Breast Cancer Group (DBCG) clinical database, we included 65,117 females with unilateral stage I-III BC diagnosed in 2000-2017, of whom 9,125 (14%) were BRCA tested.
J Am Soc Cytopathol
January 2025
Department of Pathology and Genomic Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania; Department of Pathology & Laboratory Medicine, University of Miami Hospital, Miami, Florida.
Introduction: Human epidermal growth factor receptor 2 (HER2)-low breast cancer, defined by HER2 immunohistochemistry scores of 1+ or 2+ without gene amplification, represents a unique subgroup with emerging therapeutic implications. Limited data describe the behavior of HER2-low tumors, particularly in metastatic settings. This study evaluated the frequency of HER2-low expression, Ki-67 proliferation index, and survival outcomes across HER2 subtypes in metastatic breast carcinoma using cytology specimens.
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