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A Robust Discovery Platform for the Identification of Novel Mediators of Melanoma Metastasis
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A Robust Discovery Platform for the Identification of Novel Mediators of Melanoma Metastasis

Published on: March 8, 2022

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

Jose L Orgaz1, Eva Crosas-Molist1, Amine Sadok2

  • 1Barts Cancer Institute, Queen Mary University of London, John Vane Science Building, Charterhouse Square, London EC1M 6BQ, UK; Randall Division of Cell and Molecular Biophysics, King's College London, New Hunt's House, Guy's Campus, London SE1 1UL, UK.

Cancer Cell
|January 15, 2020
PubMed

Insights

Melanoma cells develop resistance to MAPK inhibitors by altering ROCK-myosin II activity. Inhibiting this pathway kills resistant cells and enhances cancer therapies.

Area of Science:

  • Oncology
  • Cell Biology
  • Cancer Research

Background:

  • Targeted therapies and immune checkpoint blockade offer clinical benefits for melanoma but are limited by acquired resistance.
  • Understanding resistance mechanisms is crucial for improving melanoma treatment efficacy.

Purpose of the Study:

  • To investigate the role of the ROCK-myosin II pathway in the development of resistance to MAPK inhibitors in melanoma.
  • To determine if targeting the ROCK-myosin II pathway can overcome therapy resistance and improve treatment outcomes.

Main Methods:

  • Analysis of cytoskeletal remodeling and ROCK-myosin II pathway activity in melanoma cells during acquired resistance.
  • Assessment of cell survival and sensitivity to therapy upon ROCK-myosin II pathway modulation.
  • Evaluation of the impact of ROCK-myosin II inhibition on reactive oxygen species, DNA damage, and immunosuppression.

Main Results:

  • Acquisition of resistance to MAPK inhibitors involves cytoskeletal remodeling and altered ROCK-myosin II pathway activity.
  • Drug-resistant melanoma clones restore myosin II activity for survival, correlating with aggressiveness.
  • ROCK-myosin II inhibition specifically eliminates resistant cells by inducing lethal reactive oxygen species and DNA damage.
  • ROCK-myosin II ablation also reduces myeloid and lymphoid immunosuppression.

Conclusions:

  • The ROCK-myosin II pathway is a critical determinant of survival in therapy-resistant melanoma.
  • Targeting ROCK-myosin II represents a promising strategy to overcome resistance to MAPK inhibitors and immunotherapy.
  • Combining ROCK inhibitors with existing targeted therapies and immunotherapies may enhance clinical efficacy in melanoma.
Keywords:
MAPKRho-kinasecytoskeletal remodelingimmunotherapymelanoma therapy resistancemyosin IIphosphoproteomics and transcriptomicsregulatory T cellstranscriptional rewiringtumor-promoting macrophages

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