Myosin II Reactivation and Cytoskeletal Remodeling as a Hallmark and a Vulnerability in Melanoma Therapy Resistance
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Myosin II Reactivation and Cytoskeletal Remodeling as a Hallmark and a Vulnerability in Melanoma Therapy Resistance. / Orgaz, Jose L; Crosas-Molist, Eva; Sadok, Amine; Perdrix-Rosell, Anna; Maiques, Oscar; Rodriguez-Hernandez, Irene; Monger, Jo; Mele, Silvia; Georgouli, Mirella; Bridgeman, Victoria; Karagiannis, Panagiotis; Lee, Rebecca; Pandya, Pahini; Boehme, Lena; Wallberg, Fredrik; Tape, Chris; Karagiannis, Sophia N; Malanchi, Ilaria; Sanz-Moreno, Victoria.
in: CANCER CELL, Jahrgang 37, Nr. 1, 13.01.2020, S. 85-103.e9.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Myosin II Reactivation and Cytoskeletal Remodeling as a Hallmark and a Vulnerability in Melanoma Therapy Resistance
AU - Orgaz, Jose L
AU - Crosas-Molist, Eva
AU - Sadok, Amine
AU - Perdrix-Rosell, Anna
AU - Maiques, Oscar
AU - Rodriguez-Hernandez, Irene
AU - Monger, Jo
AU - Mele, Silvia
AU - Georgouli, Mirella
AU - Bridgeman, Victoria
AU - Karagiannis, Panagiotis
AU - Lee, Rebecca
AU - Pandya, Pahini
AU - Boehme, Lena
AU - Wallberg, Fredrik
AU - Tape, Chris
AU - Karagiannis, Sophia N
AU - Malanchi, Ilaria
AU - Sanz-Moreno, Victoria
N1 - Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
PY - 2020/1/13
Y1 - 2020/1/13
N2 - 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.
AB - 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.
U2 - 10.1016/j.ccell.2019.12.003
DO - 10.1016/j.ccell.2019.12.003
M3 - SCORING: Journal article
C2 - 31935375
VL - 37
SP - 85-103.e9
JO - CANCER CELL
JF - CANCER CELL
SN - 1535-6108
IS - 1
ER -