Integrated genomic analyses in PDX model reveal a cyclin-dependent kinase inhibitor Palbociclib as a novel candidate drug for nasopharyngeal carcinoma

Cheng Lung Hsu, Kar Wai Lui, Lang Ming Chi, Yung Chia Kuo, Yin Kai Chao, Chun Nan Yeh, Li Yu Lee, Yenlin Huang, Tung Liang Lin, Mei Yuan Huang, Yi Ru Lai, Yuan Ming Yeh, Hsien Chi Fan, An Chi Lin, Yen Jung Lu, Chia Hsun Hsieh, Kai Ping Chang, Ngan Ming Tsang, Hung Ming Wang, Alex Y. ChangYu Sun Chang, Hsin Pai Li

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Patient-derived xenograft (PDX) tumor model has become a new approach in identifying druggable tumor mutations, screening and evaluating personalized cancer drugs based on the mutated targets. Methods: We established five nasopharyngeal carcinoma (NPC) PDXs in mouse model. Subsequently, whole-exome sequencing (WES) and genomic mutation analyses were performed to search for genetic alterations for new drug targets. Potential drugs were applied in two NPC PDX mice model to assess their anti-cancer activities. RNA sequencing and transcriptomic analysis were performed in one NPC PDX mice to correlate with the efficacy of the anti-cancer drugs. Results: A relative high incident rate of copy number variations (CNVs) of cell cycle-associated genes. Among the five NPC-PDXs, three had cyclin D1 (CCND1) amplification while four had cyclin-dependent kinase inhibitor CDKN2A deletion. Furthermore, CCND1 overexpression was observed in > 90% FFPE clinical metastatic NPC tumors (87/91) and was associated with poor outcomes. CNV analysis disclosed that plasma CCND1/CDKN2A ratio is correlated with EBV DNA load in NPC patients' plasma and could serve as a screening test to select potential CDK4/6 inhibitor treatment candidates. Based on our NPC PDX model and RNA sequencing, Palbociclib, a cyclin-dependent kinase inhibitor, proved to have anti-tumor effects by inducing G1 arrest. One NPC patient with liver metastatic was treated with Palbociclib, had stable disease response and a drop in Epstein Barr virus (EBV) EBV titer. Conclusions: Our integrated information of sequencing-based genomic studies and tumor transcriptomes with drug treatment in NPC-PDX models provided guidelines for personalized precision treatments and revealed a cyclin-dependent kinase inhibitor Palbociclib as a novel candidate drug for NPC.

Original languageEnglish (US)
Article number233
JournalJournal of Experimental and Clinical Cancer Research
Volume37
Issue number1
DOIs
StatePublished - Sep 20 2018
Externally publishedYes

Keywords

  • CDK4/6 inhibitor
  • EBV
  • Nasopharyngeal carcinoma
  • Patient derived xenograft
  • RNA sequencing
  • Whole-exome sequencing

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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