Dual CDK4/6–PI3K/mTOR inhibition reinforces cytostatic programs and tumor control in preclinical models of primary and metastatic osteosarcoma
Year: 2026
Type: article
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 improve tumor control in preclinical OS models. In vitro sensitivity analyses using palbociclib and voxtalisib demonstrated additive to synergistic OS growth suppression, with palbociclib inducing G1 arrest and senescence, and the combination enhancing autophagy. Furthermore, the efficacy, tolerability, and mechanisms of palbociclib and voxtalisib, alone or in combination, were evaluated in molecularly defined primary treatment-naïve, and relapsed/metastatic OS models. In the relapsed/metastatic PDX77-TT2 model, short-term palbociclib exposure activated PI3K/mTOR signaling, whereas the combination of palbociclib and voxtalisib in long-term studies produced marked tumor suppression and extended survival. In the primary treatment-naïve PDX96 model, long-term palbociclib exposure generated a robust CDK4/6 pharmacodynamic response. The addition of voxtalisib reinforced autophagy, sustained CDK pathway inhibition, and improved overall tumor control. In an OS lung-colonization model, CDK4/6 inhibition alone markedly reduced OS lung nodules, with combination therapy providing comparable suppression. Dual CDK4/6-PI3K/mTOR inhibition achieves tumor control across various OS models, supporting the use of genomically guided, pathway-targeted strategies for pediatric and AYA OS.
Source: Neoplasia
Authors: Farinaz Barghi, M. Reza Saadatzadeh, Erika A. Dobrota, Harlan E. Shannon, Barbara J. Bailey, Courtney Young, Rada Malko, Ryli Justice, Niknam Riyahi, Christopher Davis, Khadijeh Bijangi-Vishehsaraei, Keiko Kreklau, Lauren K. Stevens, Jenna Koenig, Shirzat Sulayman, Sheng Liu, Jun Wan, Melissa A. Trowbridge, Kathy Coy, Felicia M. Kennedy, Anthony L. Sinn, Marissa Just, Kyle W. Jackson, George Sandusky, L. Daniel Wurtz, Christopher D. Collier, Dana Mitchell, Emily E. Seiden, Edward M. Greenfield, Emma Doud, Amber Mosley, Steven P. Angus, Michael J. Ferguson, Pankita H. Pandya, Karen E. Pollok
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,530
Funders: U.S. Department of Defense, American Cancer Society, Sarcoma Foundation of America, American Chemical Society, Indiana University, Indiana Clinical and Translational Sciences Institute, Riley Children's Foundation, National Institutes of Health, School of Medicine, Indiana University, National Cancer Institute, National Institute of Child Health and Human Development, National Center for Advancing Translational Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development, DOD Peer Reviewed Cancer Research Program
Awards: G1628476732, G6808781728, G7563707230
OpenAlex ID: W7124239565