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

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

SUBMITTER: Prada E 

PROVIDER: S-EPMC12592724 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature