AMBRA1 levels predict resistance to MAPK inhibitors in melanoma.

Autor:	Di Leo L; Melanoma Research Team, Center for Autophagy, Recycling and Disease, Danish Cancer Institute, Copenhagen 2100, Denmark., Pagliuca C; Melanoma Research Team, Center for Autophagy, Recycling and Disease, Danish Cancer Institute, Copenhagen 2100, Denmark., Kishk A; Department of Life Sciences and Medicine, University of Luxembourg, Belvaux 4365, Luxembourg., Rizza S; Redox Biology Group, Danish Cancer Institute, Copenhagen 2100, Denmark., Tsiavou C; Melanoma Research Team, Center for Autophagy, Recycling and Disease, Danish Cancer Institute, Copenhagen 2100, Denmark., Pecorari C; Redox Biology Group, Danish Cancer Institute, Copenhagen 2100, Denmark., Dahl C; Molecular Diagnostics Group, Danish Cancer Institute, Copenhagen 2100, Denmark., Pacheco MP; Department of Life Sciences and Medicine, University of Luxembourg, Belvaux 4365, Luxembourg., Tholstrup R; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense 5230, Denmark., Brewer JR; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense 5230, Denmark., Berico P; Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016., Hernando E; Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016., Cecconi F; Cell Stress and Survival, Center for Autophagy, Recycling and Disease, Danish Cancer Institute, Copenhagen 2100, Denmark.; Faculty of Medicine and Surgery, Università Cattolica del 'Sacro Cuore', Fondazione Policlinico Gemelli-Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Rome 00136, Italy., Ballotti R; Université Côte d'Azur, Nice 06200, France.; Inserm, Biology and Pathologies of melanocytes, team1, Equipe labellisée Ligue 2020, Centre Méditerranéen de Médecine Moléculaire, Nice 06200, France., Bertolotto C; Université Côte d'Azur, Nice 06200, France.; Inserm, Biology and Pathologies of melanocytes, team1, Equipe labellisée Ligue 2020, Centre Méditerranéen de Médecine Moléculaire, Nice 06200, France., Filomeni G; Redox Biology Group, Danish Cancer Institute, Copenhagen 2100, Denmark., Gjerstorff MF; Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense 5230, Denmark.; Department of Oncology, Odense University Hospital, Odense 5000, Denmark., Sauter T; Department of Life Sciences and Medicine, University of Luxembourg, Belvaux 4365, Luxembourg., Lovat P; Translational and Clinical Research Institute, Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom., Guldberg P; Molecular Diagnostics Group, Danish Cancer Institute, Copenhagen 2100, Denmark.; Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense 5230, Denmark., De Zio D; Melanoma Research Team, Center for Autophagy, Recycling and Disease, Danish Cancer Institute, Copenhagen 2100, Denmark.; Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense 5230, Denmark.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Jun 18; Vol. 121 (25), pp. e2400566121. Date of Electronic Publication: 2024 Jun 13.
DOI:	10.1073/pnas.2400566121
Abstrakt:	Intrinsic and acquired resistance to mitogen-activated protein kinase inhibitors (MAPKi) in melanoma remains a major therapeutic challenge. Here, we show that the clinical development of resistance to MAPKi is associated with reduced tumor expression of the melanoma suppressor Autophagy and Beclin 1 Regulator 1 (AMBRA1) and that lower expression levels of AMBRA1 predict a poor response to MAPKi treatment. Functional analyses show that loss of AMBRA1 induces phenotype switching and orchestrates an extracellular signal-regulated kinase (ERK)-independent resistance mechanism by activating focal adhesion kinase 1 (FAK1). In both in vitro and in vivo settings, melanomas with low AMBRA1 expression exhibit intrinsic resistance to MAPKi therapy but higher sensitivity to FAK1 inhibition. Finally, we show that the rapid development of resistance in initially MAPKi-sensitive melanomas can be attributed to preexisting subclones characterized by low AMBRA1 expression and that cotreatment with MAPKi and FAK1 inhibitors (FAKi) effectively prevents the development of resistance in these tumors. In summary, our findings underscore the value of AMBRA1 expression for predicting melanoma response to MAPKi and supporting the therapeutic efficacy of FAKi to overcome MAPKi-induced resistance. Competing Interests: Competing interests statement:P.L. is Chief Scientific Officer for AMLo Biosciences Ltd.
Databáze:	MEDLINE
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