Abstract
BackgroundRecent genomic analyses revealed that druggable molecule targets were only detectable in approximately 6% of patients with nasopharyngeal carcinoma (NPC). However, a dependency on dysregulated CDK4/6–cyclinD1 pathway signaling is an essential event in the pathogenesis of NPC. In this study, we aimed to evaluate the therapeutic efficacy of a specific CDK4/6 inhibitor, palbociclib, and its compatibility with other chemotherapeutic drugs for the treatment of NPC by using newly established xenograft models and cell lines derived from primary, recurrent, and metastatic NPC.MethodsWe evaluated the efficacies of palbociclib monotherapy and concurrent treatment with palbociclib and cisplatin or suberanilohydroxamic acid (SAHA) in NPC cell lines and xenograft models. RNA sequencing was then used to profile the drug response–related pathways. Palbociclib-resistant NPC cell lines were established to determine the potential use of cisplatin as a second-line treatment after the development of palbociclib resistance. We further examined the efficacy of palbociclib treatment against cisplatin-resistant NPC cells.ResultsIn NPC cells, palbociclib monotherapy was confirmed to induce cell cycle arrest in the G1 phase in vitro. Palbociclib monotherapy also had significant inhibitory effects in all six tested NPC tumor models in vivo, as indicated by substantial reductions in the total tumor volumes and in Ki-67 proliferation marker expression. In NPC cells, concurrent palbociclib treatment mitigated the cytotoxic effect of cisplatin in vitro. Notably, concurrent treatment with palbociclib and SAHA synergistically promoted NPC cell death both in vitro and in vivo. This combination also further inhibited tumor growth by inducing autophagy-associated cell death. NPC cell lines with induced palbociclib or cisplatin resistance remained sensitive to treatment with cisplatin or palbociclib, respectively.ConclusionsOur study findings provide essential support for the use of palbociclib as an alternative therapy for NPC and increase awareness of the effective timing of palbociclib administration with other chemotherapeutic drugs. Our results provide a foundation for the design of first-in-human clinical trials of palbociclib regimens in patients with NPC.
Highlights
Recent genomic analyses revealed that druggable molecule targets were only detectable in approximately 6% of patients with nasopharyngeal carcinoma (NPC)
Our results provide a foundation for the design of first-in-human clinical trials of palbociclib regimens in patients with NPC
We first examined the levels of p16, cyclin D1, phospho-RBSer780 and other relevant proteins in lysates of NPC cell lines and immortalized nasopharyngeal epithelial (NPE) cell line grown in both 2D monolayer and 3D spheroid cultures for 3 days (Fig. 1a)
Summary
Recent genomic analyses revealed that druggable molecule targets were only detectable in approximately 6% of patients with nasopharyngeal carcinoma (NPC). The detection of HeLa cell’s and HPV18’s genomic materials in these cell lines has cast doubt on the cellular origins [7] and has limited the applications of these lines in evaluations of novel therapeutic agents against NPC. To address this limitation, we have established new NPC xenografts and cell lines for in vivo and in vitro investigations, including Xeno and Xeno (xenografts derived from primary NPC [8];), Xeno and NPC43 (a xenograft and cell line respectively derived from recurrent NPC [8];) and C17 (NPC cell line derived from a xenograft of metastatic NPC [9]; ). Together with the conventional NPC cell line C666–1, these newly established NPC xenografts and cell lines represent a comprehensive panel of preclinical NPC models available to assess chemotherapeutic drug efficacy
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