Myosin II Reactivation and Cytoskeletal Remodeling as a Hallmark and a Vulnerability in Melanoma Therapy Resistance
Year: 2020
Type: article
Abstract: Despite substantial clinical benefit of targeted and immune checkpoint blockade-based therapies in melanoma, resistance inevitably develops. We show cytoskeletal remodeling and changes in expression and activity of ROCK-myosin II pathway during acquisition of resistance to MAPK inhibitors. MAPK regulates myosin II activity, but after initial therapy response, drug-resistant clones restore myosin II activity to increase survival. High ROCK-myosin II activity correlates with aggressiveness, identifying targeted therapy- and immunotherapy-resistant melanomas. Survival of resistant cells is myosin II dependent, regardless of the therapy. ROCK-myosin II ablation specifically kills resistant cells via intrinsic lethal reactive oxygen species and unresolved DNA damage and limits extrinsic myeloid and lymphoid immunosuppression. Efficacy of targeted therapies and immunotherapies can be improved by combination with ROCK inhibitors.
Source: Cancer Cell
Authors: Jose L. Orgaz, Eva Crosas-Molist, Amine Sadok, Anna Perdrix-Rosell, Oscar Maiques, Irene Rodriguez-Hernandez, Jo Monger, Silvia Mele, Mirella Georgouli, Victoria Bridgeman, Panagiotis Karagiannis, Rebecca Lee, Pahini Pandya, Lena Boehme, Fredrik Wallberg, Chris Tape, Sophia N. Karagiannis, Ilaria Malanchi, Victoria Sanz-Moreno
Institutions: Queen Mary University of London, King's College London, Barts Cancer Institute, Institute of Cancer Research, Cancer Research UK, The Francis Crick Institute, St Thomas' Hospital, Universität Hamburg, University Medical Center Hamburg-Eppendorf, Cancer Research UK Manchester Institute, University College London
Language: English
Topic: Melanoma and MAPK Pathways
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,200
Funders: Harry J. Lloyd Charitable Trust, Fundación Ramón Areces, Wellcome Trust, Francis Crick Institute, NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research, Barts Charity, Cancer Research UK, National Institute for Health and Care Research, Royal Society, King's College London, Horizon 2020 Framework Programme, Imperial Experimental Cancer Medicine Centre, Medical Research Council, H2020 Marie Skłodowska-Curie Actions
Awards: G182908367, G1990606676, G2210184154, G2387375797, G3063922784, G3119594665, G3282698938, G3291143030, G3345895242, G353743561, G3548643007, G3600932460, G3634344204, G3677322498, G3799972128, G3812192522, G4496151500, G4796615859, G4879218494, G4925855064, G508714220, G51288524, G526393511, G5413057595, G5812294390, G5841612952, G5848717864, G5885406002, G6206044308, G6528389704, G6552948620, G6580395194, G6684864072, G691653947, G7459165899, G7768845693, G7796927425, G7857189680, G8058084215, G814114247, G8298313232, G8314970833, G8879389441, G911949026
OpenAlex ID: W2999995352