1. Myosin II Reactivation and Cytoskeletal Remodeling as a Hallmark and a Vulnerability in Melanoma Therapy Resistance
- Author
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Silvia Mele, Jo Monger, Sophia N. Karagiannis, Panagiotis Karagiannis, Mirella Georgouli, Lena Boehme, Oscar Maiques, Anna Perdrix-Rosell, Victoria L. Bridgeman, Amine Sadok, Victoria Sanz-Moreno, Rebecca Lee, Irene Rodriguez-Hernandez, Ilaria Malanchi, Fredrik Wallberg, Jose L. Orgaz, Pahini Pandya, Eva Crosas-Molist, and Christopher J. Tape
- Subjects
0301 basic medicine ,MAPK/ERK pathway ,Male ,Cancer Research ,medicine.medical_treatment ,Mice, SCID ,VEMURAFENIB ,T-Lymphocytes, Regulatory ,B7-H1 Antigen ,regulatory T cells ,Targeted therapy ,ACTIVATION ,Mice ,0302 clinical medicine ,Mice, Inbred NOD ,Myosin ,Medicine and Health Sciences ,Tumor Microenvironment ,Medicine ,cytoskeletal remodeling ,Rho-associated protein kinase ,Melanoma ,Cytoskeleton ,rho-Associated Kinases ,melanoma therapy resistance ,Manchester Cancer Research Centre ,transcriptional rewiring ,phosphoproteomics and transcriptomics ,Stem Cells ,Cell Cycle ,3. Good health ,tumor-promoting macrophages ,Treatment Outcome ,Oncology ,BRAF INHIBITOR RESISTANCE ,INDUCED TRANSCRIPTION ,030220 oncology & carcinogenesis ,Female ,immunotherapy ,Genetics & Genomics ,EXPRESSION ,Model organisms ,Proto-Oncogene Proteins B-raf ,DNA damage ,MAP Kinase Signaling System ,Mice, Nude ,RHO-GTPASES ,Article ,MECHANISMS ,03 medical and health sciences ,myosin II ,Cell Line, Tumor ,KINASE ,Animals ,Humans ,MEK INHIBITION ,Rho-kinase ,Protein Kinase Inhibitors ,Myosin Type II ,business.industry ,ResearchInstitutes_Networks_Beacons/mcrc ,Cell Biology ,Immunotherapy ,Tumour Biology ,medicine.disease ,MAPK ,Immune checkpoint ,Mice, Inbred C57BL ,Oxidative Stress ,030104 developmental biology ,Drug Resistance, Neoplasm ,Cancer research ,business ,Reactive Oxygen Species ,ACQUIRED-RESISTANCE ,DNA Damage - Abstract
Summary 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., Graphical Abstract, Highlights • Therapy-resistant melanoma cells restore myosin II activity to increase survival • High myosin II activity identifies targeted and immunotherapy-resistant melanomas • ROCK-myosin II inhibition increases ROS-DNA damage and decreases PD-L1 and Tregs • ROCK inhibition enhances efficacy of MAPK inhibitors and immunotherapies, 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.
- Published
- 2018
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