Cited by 151Melanoma and MAPK PathwaysCancer Immunotherapy and BiomarkersProtein Kinase Regulation and GTPase Signaling

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

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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·2020·Cancer Cell

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.

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Authors
Orgaz, J. L., Crosas-Molist, E., Sadok, A., Perdrix-Rosell, A., Maiques, O., Rodriguez-Hernandez, I., Monger, J., Mele, S., Georgouli, M., Bridgeman, V., Karagiannis, P., Lee, R., Pandya, P., Boehme, L., Wallberg, F., Tape, C., Karagiannis, S. N., Malanchi, I., & Sanz-Moreno, V.
Affiliations
  • Institute of Cancer Research (GB)
  • Queen Mary University of London (GB)
  • St Thomas' Hospital (GB)
  • King's College London (GB)
  • The Francis Crick Institute (GB)
  • Cancer Research UK Manchester Institute (GB)
Venue
Cancer Cell
Publisher
Elsevier BV
Published
2020-01
Volume
37
Issue
1
Pages
85-103.e9
ISSN
1535-6108 (ISSN-L)
OpenAlex
W2999995352
Cited by
151
References
10
Citations by year
2026: 16 · 2025: 19 · 2024: 25 · 2023: 32 · 2022: 21 · 2021: 24 · 2020: 14
FWCI
7.29
Type
journal article
Language
en
Open access
Locations
  • Cancer Cell (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Ghent University Academic Bibliography (Ghent University) (submittedVersion, cc-by)
  • Research Portal (King's College London) (submittedVersion, cc-by)
  • UCL Discovery (University College London) (submittedVersion)
  • Figshare (submittedVersion, cc-by)
  • Research Explorer (The University of Manchester) (submittedVersion, other-oa)
  • The Francis Crick Institute (cc-by)
Funders
  • Royal Society
  • National Institute for Health Research
  • Fundación Ramón Areces
  • H2020 Marie Skłodowska-Curie Actions
  • Francis Crick Institute
  • Harry J. Lloyd Charitable Trust
  • Cancer Research UK
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
melanoma, treatment resistance, myosin II, cytoskeletal remodeling, MAPK inhibitors, drug resistance, reactive oxygen species, DNA damage, immunosuppression, myeloid cells, lymphoid cells, ROCK inhibitor, combination therapy, targeted therapy, immune checkpoint blockade
MeSH terms
Animals, Cell Cycle, Cytoskeleton, DNA Damage, Female, Humans, Immunotherapy, Male, Melanoma, Mice, Inbred C57BL, Mice, Nude, Mice, SCID, Mice, Inbred NOD, Treatment Outcome, Reactive Oxygen Species, Oxidative Stress, Drug Resistance, Neoplasm, MAP Kinase Signaling System, Myosin Type II, Cell Line, Tumor, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, T-Lymphocytes, Regulatory, Mice, rho-Associated Kinases, Tumor Microenvironment, B7-H1 Antigen

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