The non-muscle Myosin II cytoskeleton as a new vulnerability in therapy-resistant melanoma
| Autor: | Orgaz, José L., Crosas-Molist, Eva, Sadok, Amine, Perdrix-Rosell, Anna, Maiques, Óscar, Rodriguez-Hernandez, Irene, Monger, Jo, Lee, Rebecca, Wallberg, Fredrik, Tape, Chris |
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| Rok vydání: | 2022 |
| Popis: | Trabajo presentado en el 19th International Congress of the Society For Melanoma Research, celebrado en Edimburgo (Escocia) del 17 al 20 de octubre de 2022. MAPK-targeted therapies (MAPKi) and immune checkpoint blockers (ICB) improve survival of subsets of melanoma patients. However, therapy resistance is a persistent problem. Cross-resistance to MAPKi and ICB may be driven by common transcriptomic alterations in pathways controlling invasion and metastasis. We find that adaptation to treatment and acquisition of resistance to MAPKi involve cytoskeletal remodelling and changes in expression levels in the ROCK-non-muscle Myosin II (NMII) pathway, which is essential for cancer invasion and metastasis. Persister cells overactivate NMII to increase survival, and this becomes a vulnerability, since survival of MAPKiand ICB-resistant cells is highly dependent on ROCK-NMII. Efficacy of MAPKi and ICB can be improved by combination with ROCK inhibitors, which have a dual action by impairing melanoma cell survival (through induction of lethal reactive oxygen species and unresolved DNA damage) and reducing myeloid- and lymphoiddriven immunosuppression, ultimately overcoming cross-resistance. In human tumours, high ROCK-NMII levels identify MAPKi-, ICB-resistant melanomas, and treatment-naïve melanomas with worse prognosis. Therefore, a subset of MAPKi- and ICB-resistant melanomas is more susceptible to ROCK-NMII blockade, suggesting clinical opportunities for combination therapies. |
| Databáze: | OpenAIRE |
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