LKB1-SIK2 loss drives uveal melanoma proliferation and hypersensitivity to SLC8A1 and ROS inhibition.

Sarah Proteau, Imène Krossa, Chrystel Husser, Maxime Guéguinou, Federica Sella, Karine Bille, Marie Irondelle, Mélanie Dalmasso, Thibault Barouillet, Yann Cheli, Céline Pisibon, Nicole Arrighi, Sacha Nahon-Estève, Arnaud Martel, Lauris Gastaud, Sandra Lassalle, Olivier Mignen, Patrick Brest, Nathalie M Mazure, Frédéric Bost, Stéphanie Baillif, Solange Landreville, Simon Turcotte, Dan Hasson, Saul Carcamo, Christophe Vandier, Emily Bernstein, Laurent Yvan-Charvet, Mitchell P Levesque, Robert Ballotti, Corine Bertolotto, Thomas Strub

Journal: EMBO molecular medicine 2023;15(12):e17719

PMID: 37966164

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Abstract

Metastatic uveal melanomas are highly resistant to all existing treatments. To address this critical issue, we performed a kinome-wide CRISPR-Cas9 knockout screen, which revealed the LKB1-SIK2 module in restraining uveal melanoma tumorigenesis. Functionally, LKB1 loss enhances proliferation and survival through SIK2 inhibition and upregulation of the sodium/calcium (Na /Ca ) exchanger SLC8A1. This signaling cascade promotes increased levels of intracellular calcium and mitochondrial reactive oxygen species, two hallmarks of cancer. We further demonstrate that combination of an SLC8A1 inhibitor and a mitochondria-targeted antioxidant promotes enhanced cell death efficacy in LKB1- and SIK2-negative uveal melanoma cells compared to control cells. Our study also identified an LKB1-loss gene signature for the survival prognostic of patients with uveal melanoma that may be also predictive of response to the therapy combination. Our data thus identify not only metabolic vulnerabilities but also new prognostic markers, thereby providing a therapeutic strategy for particular subtypes of metastatic uveal melanoma.

Address: University Côte d'Azur, Nice, France.; Inserm, Biology and Pathologies of melanocytes, team1, Equipe labellisée Ligue 2020, and Equipe labellisée ARC 2022, Mediterranean Centre for Molecular Medicine, Nice, France.; University of Tours, Tours, France.; Inserm, N2C UMR 1069, Tours, France.; Department of Dermatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.; University Côte d'Azur, Nice, France.; Inserm, Hematometabolism and metainflammation, team 13, Mediterranean Centre for Molecular Medicine, Nice, France.; University Côte d'Azur, Nice, France.; Department of Ophthalmology, Centre Hospitalier Universitaire of Nice, Nice, France.; Centre Antoine Lacassagne, Nice, France.; University Côte d'Azur, Nice, France.; Laboratory of Clinical and Experimental Pathology, University Hospital of Nice, FHU OncoAge, Cote d'Azur University, Biobank BB-0033-00025, IRCAN team 4, OncoAge FHU, Nice, France.; LBAI, UMR1227, Univ Brest, Inserm, Brest, France.; University Côte d'Azur, Nice, France.; IRCAN team 4, Inserm, CNRS, FHU-oncoAge, IHU-RESPIRera Nice, Nice, France.; University Côte d'Azur, Nice, France.; Inserm, Cancer, Metabolism and environment, team, Equipe labellisée Ligue 2022, Mediterranean Centre for Molecular Medicine, Nice, France.; Département d'ophtalmologie et d'ORL-CCF, Faculté de médecine, Université Laval, Quebec City, QC, Canada.; CUO-Recherche and Axe médecine régénératrice, Centre de recherche du CHU de Québec-Université Laval, Quebec City, QC, Canada.; Centre de recherche sur le cancer de l'Université Laval, Quebec City, QC, Canada.; Centre de recherche en organogénèse expérimentale de l'Université Laval/LOEX, Quebec City, QC, Canada.; Cancer Axis, Centre de recherche du Centre Hospitalier de l'Université de Montréal/Institut du cancer de Montréal, Montréal, QC, Canada.; Hepato-Pancreato-Biliary Surgery and Liver Transplantation Service, Centre hospitalier de l'Université de Montréal, Montréal, QC, Canada.; Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Tisch Cancer Institute Bioinformatics for Next Generation Sequencing (BiNGS) Facility, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; University Côte d'Azur, Nice, France.; Inserm, Hematometabolism and metainflammation, team 13, Mediterranean Centre for Molecular Medicine, Nice, France.

DOI: 10.15252/emmm.202317719