PRKG1 hinders myogenic differentiation and predicts response to AKT inhibitor ipatasertib in Rhabdomyosarcoma

Estela Prada, Pablo Táboas, Evelyn Andrades, Soledad Gómez-González, Silvia Mateo-Lozano, Alex Cebria-Xart, Pau Berenguer-Molins, Julia Perera-Bel, Juan Pablo Arcon, Suwipa Saen-Oon, Lucía Díaz, Marina Gay, Ignasi Folch-I-Casanovas, Antonia Odena, Marta Vilaseca, Quirze Rovira, Laura Garcia-Gerique, Eva Rodriguez, Carlota Rovira, Gonçalo Rodrigues, Angel M. Carcaboso, Alexandra Avgustinova, Inmaculada Hernández-Muñoz and Jaume Mora ()
Additional contact information
Estela Prada: Institut de Recerca Sant Joan de Déu (IRSJD). Esplugues de Llobregat
Pablo Táboas: Institut de Recerca Sant Joan de Déu (IRSJD). Esplugues de Llobregat
Evelyn Andrades: Hospital del Mar Research Institute (HMRIB)
Soledad Gómez-González: Institut de Recerca Sant Joan de Déu (IRSJD). Esplugues de Llobregat
Silvia Mateo-Lozano: Institut de Recerca Sant Joan de Déu (IRSJD). Esplugues de Llobregat
Alex Cebria-Xart: Institut de Recerca Sant Joan de Déu (IRSJD). Esplugues de Llobregat
Pau Berenguer-Molins: Hospital del Mar Research Institute (HMRIB)
Julia Perera-Bel: Hospital del Mar Research Institute (HMRIB)
Juan Pablo Arcon: Nostrum Biodiscovery S.L.
Suwipa Saen-Oon: Nostrum Biodiscovery S.L.
Lucía Díaz: Nostrum Biodiscovery S.L.
Marina Gay: Institute for Research in Biomedicine (IRB Barcelona). The Barcelona Institute of Science and Technology (BIST)
Ignasi Folch-I-Casanovas: Institute for Research in Biomedicine (IRB Barcelona). The Barcelona Institute of Science and Technology (BIST)
Antonia Odena: Institute for Research in Biomedicine (IRB Barcelona). The Barcelona Institute of Science and Technology (BIST)
Marta Vilaseca: Institute for Research in Biomedicine (IRB Barcelona). The Barcelona Institute of Science and Technology (BIST)
Quirze Rovira: Institut de Recerca Sant Joan de Déu (IRSJD). Esplugues de Llobregat
Laura Garcia-Gerique: Institut de Recerca Sant Joan de Déu (IRSJD). Esplugues de Llobregat
Eva Rodriguez: Hospital Sant Joan de Déu. Esplugues de Llobregat
Carlota Rovira: Hospital Sant Joan de Déu. Esplugues de Llobregat
Gonçalo Rodrigues: Institut de Recerca Sant Joan de Déu (IRSJD). Esplugues de Llobregat
Angel M. Carcaboso: Institut de Recerca Sant Joan de Déu (IRSJD). Esplugues de Llobregat
Alexandra Avgustinova: Institut de Recerca Sant Joan de Déu (IRSJD). Esplugues de Llobregat
Inmaculada Hernández-Muñoz: Institut de Recerca Sant Joan de Déu (IRSJD). Esplugues de Llobregat
Jaume Mora: Institut de Recerca Sant Joan de Déu (IRSJD). Esplugues de Llobregat

Nature Communications, 2025, vol. 16, issue 1, 1-25

Abstract: Abstract Rhabdomyosarcoma (RMS) is marked by a myogenesis differentiation blockade, and while the AKT/mTOR pathway is universally activated, its pharmacological inhibition has shown limited success. Here, we evaluate the activity of pan-AKT inhibitors Ipatasertib, ATP-competitive, and Miransertib, allosteric inhibitor, in RMS cell lines and fusion-positive/negative patient-derived xenografts (PDX). Unlike Miransertib, Ipatasertib show significant antitumor activity against a subset of RMS. Besides AKT, the other target of Ipatasertib, but not of Miransertib, is PRKG1, a cGMP-dependent protein kinase that shares the ATP binding pocket with AKT. We investigate the role of PRKG1 in PRKG1-depleted RMS cells and in xenograft models by transcriptomic approaches. PRKG1 silencing in RMS cells reduces tumor formation in xenograft models and induces a differentiated myogenic transcriptome. RMS show higher PRKG1 expression compared to any other developmental cancer, akin to fetal skeletal muscle. Importantly, PRKG1 expression in RMS correlates with mesodermal transcriptional signature and enhanced sensitivity to Ipatasertib, regardless of the fusion oncogene status. The antitumor activity of Ipatasertib is dose-dependent, reaching an effective intra-tumor concentration when administered at 25 mg/kg daily. This study unveils the role of PRKG1 in myogenesis and highlights the potential of PRKG1 as a clinical biomarker for Ipatasertib therapy in RMS.

Date: 2025
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DOI: 10.1038/s41467-025-64783-3

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