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

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

doi:10.1016/j.ccell.2019.12.003

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

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

Division of Cancer Sciences (L5)

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	85-103.e9
Journal	Cancer Cell
Volume	37
Issue number	1
DOIs	https://doi.org/10.1016/j.ccell.2019.12.003
Publication status	Published - 13 Jan 2020

Keywords

MAPK
Rho-kinase
cytoskeletal remodeling
immunotherapy
melanoma therapy resistance
myosin II
phosphoproteomics and transcriptomics
regulatory T cells
transcriptional rewiring
tumor-promoting macrophages

Research Beacons, Institutes and Platforms

Manchester Cancer Research Centre

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ccell.2019.12.003

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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. (2020). Myosin II Reactivation and Cytoskeletal Remodeling as a Hallmark and a Vulnerability in Melanoma Therapy Resistance. Cancer Cell, 37(1), 85-103.e9. https://doi.org/10.1016/j.ccell.2019.12.003

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title = "Myosin II Reactivation and Cytoskeletal Remodeling as a Hallmark and a Vulnerability in Melanoma Therapy Resistance",

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.",

keywords = "MAPK, Rho-kinase, cytoskeletal remodeling, immunotherapy, melanoma therapy resistance, myosin II, phosphoproteomics and transcriptomics, regulatory T cells, transcriptional rewiring, tumor-promoting macrophages",

author = "Orgaz, {Jose L.} and Eva Crosas-Molist and Amine Sadok and Anna Perdrix-Rosell and Oscar Maiques and Irene Rodriguez-Hernandez and Jo Monger and Silvia Mele and Mirella Georgouli and Victoria Bridgeman and Panagiotis Karagiannis and Rebecca Lee and Pahini Pandya and Lena Boehme and Fredrik Wallberg and Chris Tape and Karagiannis, {Sophia N.} and Ilaria Malanchi and Victoria Sanz-Moreno",

year = "2020",

month = jan,

day = "13",

doi = "10.1016/j.ccell.2019.12.003",

language = "English",

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pages = " 85--103.e9",

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Orgaz, JL, 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, SN, Malanchi, I & Sanz-Moreno, V 2020, 'Myosin II Reactivation and Cytoskeletal Remodeling as a Hallmark and a Vulnerability in Melanoma Therapy Resistance', Cancer Cell, vol. 37, no. 1, pp. 85-103.e9. https://doi.org/10.1016/j.ccell.2019.12.003

TY - JOUR

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

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. 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.

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. 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.

KW - MAPK

KW - Rho-kinase

KW - cytoskeletal remodeling

KW - immunotherapy

KW - melanoma therapy resistance

KW - myosin II

KW - phosphoproteomics and transcriptomics

KW - regulatory T cells

KW - transcriptional rewiring

KW - tumor-promoting macrophages

U2 - 10.1016/j.ccell.2019.12.003

DO - 10.1016/j.ccell.2019.12.003

M3 - Article

C2 - 31935375

SN - 1535-6108

VL - 37

SP - 85-103.e9

JO - Cancer Cell

JF - Cancer Cell

IS - 1

ER -

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

Abstract

Keywords

Research Beacons, Institutes and Platforms

UN SDGs

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