Kinome profiling of osteosarcoma patient-derived xenograft TT2 treated with palbociclib

ABSTRACT: 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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Christine Berryhill  

LAB HEAD: Karen Pollok

PROVIDER: PXD069093 | Pride | 2026-02-02

REPOSITORIES: Pride