biostudies-literatureUnknown72Barghi FOsteosarcoma (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 impNeoplasia (New York, N.Y.)101266https://www.ebi.ac.uk/biostudies/studies/S-EPMC12830294biostudies-literatureDual CDK4/6-PI3K/mTOR inhibition reinforces cytostatic programs and tumor control in preclinical models of primary and metastatic osteosarcoma.PMC12830294Collier CDYoung CStevens LKDoud EBailey BJSinn ALTrowbridge MALiu SSandusky GKoenig JSeiden EESulayman SJust MBarghi FFerguson MJDavis CWan JGreenfield EMMosley ARiyahi NKreklau KPollok KEKennedy FMMalko RAngus SPSaadatzadeh MRShannon HEPandya PHBijangi-Vishehsaraei KJustice RJackson KWDobrota EACoy KWurtz LDMitchell DfalseDual CDK4/6-PI3K/mTOR inhibition reinforces cytostatic programs and tumor control in preclinical models of primary and metastatic osteosarcoma.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 imp2026-01-01T00:00:00Z2026 Jan2026-06-06T22:00:56.256Z2026-06-05T03:12:04.512ZS-EPMC128302944154437610.1016/j.neo.2025.101266