Preclinical evaluation of ribociclib and its synergistic effect in combination with alpelisib in non-keratinizing nasopharyngeal carcinoma

摘要: Ribociclib is a specific cyclin dependent kinase (Cdk) 4/6 inhibitor that induces G1 arrest by blocking the formation of D1-Cdk4/6 complex and inhibiting retinoblastoma (RB) phosphorylation. Cyclin D1 overexpressed in over 90% nasopharyngeal carcinoma (NPC) CCND1 gene activation plays critical role NPC pathogenesis. This study evaluated preclinical activities ribociclib cell lines patient derived xenograft (PDX) models. Over 95% growth inhibition was observed at 96 hours after treatment. (IC50 concentrations: HK1 = 1.42 ± 0.23 µM; HK1-LMP1 = 2.18 ± 0.70 µM C666-1 = 8.26 ± 0.92 µM). HK1 C666-1 cells were chosen for analysis on signaling, apoptosis cycle. Treatment with 48 hours consistently showed dose-dependent reduction phosphorylated total RB expression cycle only observed. Combining alpha-specific PI3K alpelisib synergistic effect two PDX models nude mice. The co-treatment induced significant tumor volume both xeno-666 xeno-2117 compared treatment alone control (p < 0.01). In summary, active augmented when combined alpelisib. supports clinical evaluation NPC.