PRKG1 hinders myogenic differentiation and predicts response to AKT inhibitor ipatasertib in Rhabdomyosarcoma
Year: 2025
Type: article
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. Despite frequent AKT/mTOR pathway activation in patient’s rhabdomyosarcoma (RMS), success of AKT inhibitors in the clinical has been limited. Here, using RMS patient-derived models, the authors demonstrate that the efficacy of the AKT inhibitor, ipatasertib, is in part due to its off-target effects on PRKG1, identifying PRKG1 as a potential biomarker for ipatasertib response.
Source: Nature Communications
Authors: 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, Jaume Mora
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,990
OpenAlex ID: W4415958311