MAPKi; drug resistance; melanoma; mitochondria-targeted agents (MTA); prohibitins; therapeutic strategy; Prohibitins; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins B-raf; Ligands; Protein Kinase Inhibitors; Humans; Proto-Oncogene Proteins B-raf/metabolism; Protein Kinase Inhibitors/pharmacology; Drug Resistance, Neoplasm; Melanoma/pathology; Skin Neoplasms/drug therapy; Skin Neoplasms; Biochemistry, Genetics and Molecular Biology (all); General Medicine
Abstract :
[en] Despite important advances in the treatment of metastatic melanoma with the development of MAPK-targeted agents and immune checkpoint inhibitors, the majority of patients either do not respond to therapies or develop acquired resistance. Furthermore, there is no effective targeted therapy currently available for BRAF wild-type melanomas (approximately 50% of cutaneous melanoma). Thus, there is a compelling need for new efficient targeted therapies. Prohibitins (PHBs) are overexpressed in several types of cancers and implicated in the regulation of signaling networks that promote cell invasion and resistance to cell apoptosis. Herein, we show that PHBs are highly expressed in melanoma and are associated with not only poor survival but also with resistance to BRAFi/MEKi. We designed and identified novel specific PHB inhibitors that can inhibit melanoma cell growth in 3D spheroid models and a large panel of representative cell lines with different molecular subtypes, including those with intrinsic and acquired resistance to MAPKi, by significantly moderating both MAPK (CRAF-ERK axis) and PI3K/AKT pathways, and inducing apoptosis through the mitochondrial pathway and up-regulation of p53. In addition, autophagy inhibition enhances the antitumor efficacy of these PHB ligands. More important, these ligands can act in synergy with MAPKi to more efficiently inhibit cell growth and overcome drug resistance in both BRAF wild-type and mutant melanoma. In conclusion, targeting PHBs represents a very promising therapeutic strategy in melanoma, regardless of mutational status.
Disciplines :
Oncology
Author, co-author :
Najem, Ahmad ; Laboratory of Clinical and Experimental Oncology (LOCE), Institut Jules Bordet, Université Libre de Bruxelles, 1000 Brussels, Belgium
Krayem, Mohammad ; Laboratory of Clinical and Experimental Oncology (LOCE), Institut Jules Bordet, Université Libre de Bruxelles, 1000 Brussels, Belgium
Sabbah, Serena ; Laboratory of Clinical and Experimental Oncology (LOCE), Institut Jules Bordet, Université Libre de Bruxelles, 1000 Brussels, Belgium
Pesetti, Matilde; Laboratory of Clinical and Experimental Oncology (LOCE), Institut Jules Bordet, Université Libre de Bruxelles, 1000 Brussels, Belgium
Journe, Fabrice ; Université de Mons - UMONS > Faculté de Médecine et de Pharmac > Service d'Anatomie humaine et Oncologie expérimentale ; Laboratory of Clinical and Experimental Oncology (LOCE), Institut Jules Bordet, Université Libre de Bruxelles, 1000 Brussels, Belgium
Awada, Ahmad ; Laboratory of Clinical and Experimental Oncology (LOCE), Institut Jules Bordet, Université Libre de Bruxelles, 1000 Brussels, Belgium ; Department of Medical Oncology, Institut Jules Bordet, Université Libre de Bruxelles, 1070 Brussels, Belgium
Désaubry, Laurent ; Center of Research in Biomedicine of Strasbourg, Regenerative Nanomedicine (UMR 1260), INSERM, University of Strasbourg, 67000 Strasbourg, France
Ghanem, Ghanem E; Laboratory of Clinical and Experimental Oncology (LOCE), Institut Jules Bordet, Université Libre de Bruxelles, 1000 Brussels, Belgium
Language :
English
Title :
Targeting Prohibitins to Inhibit Melanoma Growth and Overcome Resistance to Targeted Therapies.
Publication date :
14 July 2023
Journal title :
Cells
eISSN :
2073-4409
Publisher :
Multidisciplinary Digital Publishing Institute (MDPI), Switzerland
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