Dual CDK4/6-PI3K/mTOR inhibition reinforces cytostatic programs and tumor control in preclinical models of primary and metastatic osteosarcoma.

ABSTRACT: Osteosarcoma (OS) in pediatric, adolescent, and young adult (AYA) patients is an aggressive bone cancer with limited treatment options. Dysregulation of the CDK4/6-cyclin D axis and the PI3K/mTOR pathway contributes to OS pathogenesis, providing a biological rationale for co-targeting these signaling nodes. However, pharmacologic CDK4/6 inhibition can trigger compensatory activation of the PI3K/mTOR pathway, restoring D-type cyclin expression and partially reactivating CDK4/6 signaling. Thus, dual inhibition of the CDK4/6 and PI3K/mTOR pathways not only addresses two parallel oncogenic drivers but may also prevent potential CDK4/6 inhibitor resistance mediated by feedback activation of PI3K/mTOR. In this study, we tested the hypothesis that coordinated targeting of these pathways would imp

SUBMITTER: Barghi F 

PROVIDER: S-EPMC12830294 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature