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Myosin II Reactivation and Cytoskeletal Remodeling as a Hallmark and a Vulnerability in Melanoma Therapy Resistance

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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

Original languageEnglish
Pages (from-to)85-103.e9
JournalCANCER CELL
Volume37
Issue number1
Early online date13 Jan 2020
DOIs
Publication statusPublished - 13 Jan 2020

King's Authors

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. Orgaz et al. show that myosin II activity increases during melanoma adaptation to MAPK pathway inhibition. ROCK-myosin II signaling supports survival of resistant melanoma cells and promotes immunosuppression. ROCK inhibitors improve the efficacy of MAPK inhibitors and immunotherapies in melanoma models.

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