دورية أكاديمية
أعرض في EDS

Targeting the hedgehog transcription factors GLI1 and GLI2 restores sensitivity to vemurafenib-resistant human melanoma cells.

التفاصيل البيبلوغرافية
العنوان: Targeting the hedgehog transcription factors GLI1 and GLI2 restores sensitivity to vemurafenib-resistant human melanoma cells.
المؤلفون: Faião-Flores F; Department of Clinical Chemistry and Toxicological Analysis, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil., Alves-Fernandes DK; Department of Clinical Chemistry and Toxicological Analysis, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil., Pennacchi PC; Department of Clinical Chemistry and Toxicological Analysis, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil., Sandri S; Department of Clinical Chemistry and Toxicological Analysis, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil., Vicente AL; Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil., Scapulatempo-Neto C; Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil.; Department of Pathology, Barretos Cancer Hospital, Barretos, Brazil., Vazquez VL; Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil.; Department of Surgery Melanoma/Sarcoma, Barretos Cancer Hospital, Barretos, Brazil., Reis RM; Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil.; Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.; 3B's - PT Government Associate Laboratory, Braga/Guimarães, Guimarães, Portugal., Chauhan J; Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Headington, Oxford, UK., Goding CR; Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Headington, Oxford, UK., Smalley KS; The Department of Tumor Biology, The Moffitt Cancer Center and Research Institute, Tampa, FL, USA., Maria-Engler SS; Department of Clinical Chemistry and Toxicological Analysis, School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.
المصدر: Oncogene [Oncogene] 2017 Mar 30; Vol. 36 (13), pp. 1849-1861. Date of Electronic Publication: 2016 Oct 17.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Nature Publishing Group Country of Publication: England NLM ID: 8711562 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5594 (Electronic) Linking ISSN: 09509232 NLM ISO Abbreviation: Oncogene Subsets: MEDLINE
أسماء مطبوعة: Publication: <2002->: Basingstoke : Nature Publishing Group
Original Publication: Basingstoke, Hampshire, UK : Scientific & Medical Division, MacMillan Press, c1987-
مواضيع طبية MeSH: Drug Resistance, Neoplasm*, Antineoplastic Agents/*pharmacology , Indoles/*pharmacology , Kruppel-Like Transcription Factors/*antagonists & inhibitors , Melanoma/*metabolism , Sulfonamides/*pharmacology , Zinc Finger Protein GLI1/*antagonists & inhibitors, Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Cellular Senescence/genetics ; Gene Expression ; Gene Knockdown Techniques ; Hedgehog Proteins/metabolism ; Humans ; Kruppel-Like Transcription Factors/genetics ; Kruppel-Like Transcription Factors/metabolism ; Melanoma/drug therapy ; Melanoma/genetics ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Proto-Oncogene Proteins B-raf/antagonists & inhibitors ; Signal Transduction/drug effects ; Vemurafenib ; Zinc Finger Protein GLI1/genetics ; Zinc Finger Protein GLI1/metabolism ; Zinc Finger Protein Gli2
مستخلص: BRAF inhibitor (BRAFi) therapy for melanoma patients harboring the V600E mutation is initially highly effective, but almost all patients relapse within a few months. Understanding the molecular mechanisms underpinning BRAFi-based therapy is therefore an important issue. Here we identified a previously unsuspected mechanism of BRAFi resistance driven by elevated Hedgehog (Hh) pathway activation that is observed in a cohort of melanoma patients after vemurafenib treatment. Specifically, we demonstrate that melanoma cell lines, with acquired in vitro-induced vemurafenib resistance, show increased levels of glioma-associated oncogene homolog 1 and 2 (GLI1/GLI2) compared with naïve cells. We also observed these findings in clinical melanoma specimens. Moreover, the increased expression of the transcription factors GLI1/GLI2 was independent of canonical Hh signaling and was instead correlated with the noncanonical Hh pathway, involving TGFβ/SMAD (transforming growth factor-β/Sma- and Mad-related family) signaling. Knockdown of GLI1 and GLI2 restored sensitivity to vemurafenib-resistant cells, an effect associated with both growth arrest and senescence. Treatment of vemurafenib-resistant cells with the GLI1/GLI2 inhibitor Gant61 led to decreased invasion of the melanoma cells in a three-dimensional skin reconstruct model and was associated with a decrease in metalloproteinase (MMP2/MMP9) expression and microphthalmia transcription factor upregulation. Gant61 monotherapy did not alter the drug sensitivity of naïve cells, but could reverse the resistance of melanoma cells chronically treated with vemurafenib. We further noted that alternating dosing schedules of Gant61 and vemurafenib prevented the onset of BRAFi resistance, suggesting that this could be a potential therapeutic strategy for the prevention of therapeutic escape. Our results suggest that targeting the Hh pathway in BRAFi-resistant melanoma may represent a viable therapeutic strategy to restore vemurafenib sensitivity, reducing or even inhibiting the acquired chemoresistance in melanoma patients.
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معلومات مُعتمدة: P01 CA128814 United States CA NCI NIH HHS; P50 CA168536 United States CA NCI NIH HHS; R01 CA161107 United States CA NCI NIH HHS; R21 CA198550 United States CA NCI NIH HHS
المشرفين على المادة: 0 (Antineoplastic Agents)
0 (Hedgehog Proteins)
0 (Indoles)
0 (Kruppel-Like Transcription Factors)
0 (Protein Kinase Inhibitors)
0 (Sulfonamides)
0 (Zinc Finger Protein GLI1)
0 (Zinc Finger Protein Gli2)
207SMY3FQT (Vemurafenib)
EC 2.7.11.1 (Proto-Oncogene Proteins B-raf)
تواريخ الأحداث: Date Created: 20161018 Date Completed: 20170901 Latest Revision: 20220310
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC5378933
DOI: 10.1038/onc.2016.348
PMID: 27748762
قاعدة البيانات: MEDLINE
الوصف
تدمد:1476-5594
DOI:10.1038/onc.2016.348