Preclinical evaluation of palbociclib on newly established preclinical models of nasopharyngeal carcinoma (NPC)

Abstract

The efficacy of a selective CDK4/6 inhibitor (palbociclib) was evaluated in various preclinical models of nasopharyngeal carcinoma (NPC) including three NPC cell line (two newly established) and three newly established patient-derived xenografts (PDXs). Preclinical evaluation of novel therapeutic agents in NPC has been hampered in the past by the availability of authenticated and representative preclinical models of NPC harboring Epstein-Barr virus (EBV) infection. Hence, targeted therapy in NPC has remained grossly underdeveloped. Palbociclib has been shown to be effective in multiple human cancers. Prediction markers to the sensitivity of palbociclib treatment including (a) functional RB (retinoblastoma) signaling pathway, which regulates cell cycle progression, and (b) inactivation of p16 (an inhibitor of cell cycle progression), both of them are commonly present in NPC indicative of their responsiveness to palbociclib. In this study, the sensitivity of a series of EBV-infected NPC preclinical models to palbociclib was comprehensively assessed. The application of palbociclib in combination use with other chemotherapeutic drugs including cisplatin and SAHA to increase the treatment efficiency of NPC was explored. The palbociclib was observed to antagonize the cytotoxicity of cisplatin in NPC cells examined in vitro and is not recommended to be used in the combination treatment for NPC patients. Interestingly, concurrent use of suberoylanilide hydroxamic acid (SAHA), a histone modification agent, was shown to be effective in enhancing the treatment response of NPC cells to palbociclib both in vitro and in vivo. The results of this study support the therapeutic application of palbociclib, either alone or in combination with SAHA, for treatment of NPC. Palbociclib-resistant NPC cell lines were also established in this study and characterized. The palbociclib-resistant NPC cells has acquired alternative cell proliferation regulatory pathways independent of the CDK4/6-CyclinD1-RB pathway. Interestingly, plabociclib-resistant NPC cell lines retained their responsiveness to SAHA or cisplatin which has clinical implications in treatment of NPC. (303)