PXD069093

PXD069093 is an original dataset announced via ProteomeXchange.

Title	Kinome profiling of osteosarcoma patient-derived xenograft TT2 treated with palbociclib
Description	Osteosarcoma (OS) is the most common primary bone cancer in adolescents, young adults (AYA), and children, with up to 25% of patients developing metastatic disease, primarily in the lungs. Despite survival rates being >70% for localized tumors, patients with metastatic OS have <30% survival due to limited effective salvage therapies. OS is characterized by chromosomal instability (CINs) and dysregulated CDK4/6 and PI3K/mTOR pathways. The retinoblastoma protein (RB), a downstream target of CDK4/6, is a key regulator of G1/S cell cycle progression. We validated these targets in OS cell lines, xenografts, and patient-derived xenografts (PDXs), revealing CDK4/6 hyperactivation. While CDK4/6 inhibitors show promise, they are ineffective as monotherapies due to cytostatic effects and resistance from compensatory pathways, such as PI3K/AKT/mTOR. This study investigates dual inhibition of CDK4/6 and PI3K/mTOR using palbociclib and voxtalisib, respectively, in OS models. In RB proficient (RB+) OS lines, the combination therapy exhibited synergistic inhibition of cell growth and G1 arrest, while inducing autophagy without disrupting palbociclib-induced senescence. Prolonged treatment triggered autophagy in treatment-naïve PDXs, with senescence partially reversed in the combination group. Combination therapy enhanced palbociclib efficacy in both pretreated and naïve PDX models, improving survival. Mechanistically, palbociclib reduced CDK1/2 activity, while voxtalisib suppressed CDK1/2 and RB1 phosphorylation, impairing cell cycle progression. The combination significantly reduced metastatic burden and improved survival in OS lung colonization models, inhibiting pre-established metastatic foci. Kinome profiling and proteomic analyses confirmed decreased PI3K and mTOR activity. This study highlights the potential of CDK4/6 and PI3K/mTOR dual inhibition in OS, offering therapeutic promise for overcoming resistance and improving outcomes in pediatric and AYA patients with CDK4/6 hyperactivation.
HostingRepository	PRIDE
AnnounceDate	2026-02-02
AnnouncementXML	Submission_2026-02-01_16:36:37.239.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Christine Berryhill
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2025-10-02 11:43:35	ID requested
⏵ 1	2026-02-01 16:36:38	announced

Barghi F, Saadatzadeh MR, Dobrota EA, Shannon HE, Bailey BJ, Young C, Malko R, Justice R, Riyahi N, Davis C, Bijangi-Vishehsaraei K, Kreklau K, Stevens LK, Koenig J, Sulayman S, Liu S, Wan J, Trowbridge MA, Coy K, Kennedy FM, Sinn AL, Just M, Jackson KW, Sandusky G, Wurtz LD, Collier CD, Mitchell D, Seiden EE, Greenfield EM, Doud E, Mosley A, Angus SP, Ferguson MJ, Pandya PH, Pollok KE, Dual CDK4/6-PI3K/mTOR inhibition reinforces cytostatic programs and tumor control in preclinical models of primary and metastatic osteosarcoma. Neoplasia, 72():101266(2026) [pubmed]

10.1016/j.neo.2025.101266;

submitter keyword: Kinase, inhibitor, bead, PI3K, CDK4/6, mTOR

Karen Pollok
contact affiliation	Indiana University School of Medicine, Dept of Pediatrics; Herman B Wells Center for Pediatric Research
contact email	kpollok@iu.edu
lab head
Christine Berryhill
contact affiliation	Indiana University School of Medicine
contact email	causherm@iu.edu
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/02/PXD069093

PRIDE project URI

• PRIDE
  1. PXD069093
     1. Label: PRIDE project
     2. Name: Kinome profiling of osteosarcoma patient-derived xenograft TT2 treated with palbociclib