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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2018-12

AUTHORS

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. Chang, Yu-Sun Chang, Hsin-Pai Li

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. More... »

PAGES

233

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1186/s13046-018-0873-5

    DOI

    http://dx.doi.org/10.1186/s13046-018-0873-5

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1107121021

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/30236142


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