PXD064262

PXD064262 is an original dataset announced via ProteomeXchange.

Title	PRKG1 hinders myogenic differentiation and predicts response to AKT inhibitor Ipatasertib in Rhabdomyosarcoma
Description	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. This study stems from an effort to understand the failure to translate preclinical findings to clinical application. Here, we evaluated the activity of two pan-AKT inhibitors: Ipatasertib, an ATP-competitive inhibitor, and Miransertib, an allosteric AKT inhibitor. In vitro and in vivo efficacy assessment was conducted in RMS cell lines and fusion-positive/negative patient-derived xenografts (PDX). Unlike Miransertib, Ipatasertib showed significant antitumor activity against a subset of RMS. Besides AKT, the other kinase target of Ipatasertib, but not of Miransertib, is PRKG1, a cGMP-dependent protein kinase that shares the ATP binding pocket with AKT. The role of PRKG1 in RMS was investigated in PRKG1-depleted RMS cells and in xenograft models by transcriptomic approaches. PRKG1 silencing in RMS cells reduced tumor formation in xenograft models and induced a differentiated myogenic transcriptome. RMS showed 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.
HostingRepository	PRIDE
AnnounceDate	2025-07-16
AnnouncementXML	Submission_2025-07-16_10:02:38.681.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Marta Vilaseca
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2025-05-24 07:30:42	ID requested
⏵ 1	2025-07-16 10:02:39	announced

Dataset with its publication pending

submitter keyword: Ipatasertib

Rhabdomyosarcoma

Target Therapy

Pediatric Cancer

Myogenic differentiation.

Dr. Jaume Mora
contact affiliation	Pediatric Cancer Center Barcelona (PCCB), Hospital Sant Joan de Déu. Esplugues de Llobregat, 08950 Barcelona, Spain
contact email	Jaume.mora@sjd.es
lab head
Marta Vilaseca
contact affiliation	Mass Spectrometry & Proteomics Core Facility (MSPCF) Institute for Research in Biomedicine (IRB Barcelona) Barcelona Institute of Science and Technology (BIST) C/ Baldiri Reixac, 10-12 08028 Barcelona - Spain
contact email	masspe@irbbarcelona.org
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD064262
     1. Label: PRIDE project
     2. Name: PRKG1 hinders myogenic differentiation and predicts response to AKT inhibitor Ipatasertib in Rhabdomyosarcoma