016 | Mechanisms underlying resistance to CDK4/6 inhibitors in aggressive medulloblastoma subtypes

Alice Foti¹, Fabio Allia¹, Marilena Briglia¹, Gianpiero Tamburrini², Roberta Malaguarnera¹, Francesco Cecconi^2|3, Vittoria Pagliarini^2|3, Veronica Marabitti⁴, Francesca Nazio⁴, Adriana C.E. Graziano¹ | ¹University of Enna “Kore”, Enna, Italy; ²Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; ³Università Cattolica del Sacro Cuore, Rome, Italy; ⁴University of Rome Tor Vergata, Rome, Italy.

Medulloblastoma (MB) represents a highly heterogeneous pediatric brain tumor, both at the clinical and molecular level. Its therapeutic management is challenged by inter-subgroup heterogeneity and by the frequent occurrence of resistance to targeted therapies. Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have emerged as attractive candidates for limiting tumor cell proliferation, particularly in the treatment of breast cancer; however, both intrinsic and treatment-induced resistance significantly limit their effectiveness. The molecular events sustaining this resistance states remain incompletely understood. The present study aimed to elucidate the biological mechanisms driving variable responses CDK4/6 inhibition in two MB subgroups associated with poor prognosis (i.e. Sonic Hedgehog (SHH) and Group 3 MB). Using abemaciclib and palbociclib, we assessed drug sensitivity in a panel of subgroup-specific medulloblastoma cell lines. Differences in intracellular drug accumulation were evaluated by leveraging the intrinsic fluorescence of the compounds, enabling direct comparison of drug internalization among responsive and non-responsive models. To analyze the evolution of resistance, we established in vitro models of acquired resistance through long-term exposure of sensitive cell lines to CDK4/6 inhibitors. Molecular profiling of sensitive, intrinsically resistant, and acquired-resistant cells revealed extensive alterations in cell cycle control mechanisms, including changes in retinoblastoma protein phosphorylation, alongside dysregulation of autophagy and stemness-associated pathways. Overall, these findings shed light on resistance mechanisms to CDK4/6 inhibitors in MB and highlight potential biomarkers and therapeutic vulnerabilities that could be exploited to improve treatment efficacy in high-risk patients.
This study was supported by the European Union – NextGenerationEU, PNRR (M6/C2), grant PNRR-TR1-2023-12378243, “Novel molecular targets and innovative therapeutic perspective in medulloblastoma”.