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

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

Cancer cell (2020-01-15)
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
PMID31935375
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.

MATERIALS
Product Number
Brand
Product Description
555550
Sigma-Aldrich
Rho Kinase Inhibitor, The Rho kinase inhibitor, CAS 872543-07-6, is a cell-permeable, highly specific, reversible, potent, and ATP-competitive inhibitor of Rho-associated kinase (ROCK; Ki = 1.6 nM).
HT10132
Sigma-Aldrich
Bouin′s solution, histological fixative