Whole-exome sequencing reveals potential mechanisms of drug resistance to FGFR3-TACC3 targeted therapy and subsequent dr
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RESEARCH ARTICLE
Open Access
Whole-exome sequencing reveals potential mechanisms of drug resistance to FGFR3TACC3 targeted therapy and subsequent drug selection: towards a personalized medicine Zhou Tong1†, Cong Yan2†, Yu-An Dong3, Ming Yao3, Hangyu Zhang1, Lulu Liu1, Yi Zheng1, Peng Zhao1, Yimin Wang4, Weijia Fang1,5, Feifei Zhang6 and Weiqin Jiang1*
Abstract Background: Drug resistance is a major obstacle to effective cancer therapy. In order to detect the change in tumor genomic states under drug selection pressure, we use next-generation sequencing technology to investigate the underlying potential mechanisms of drug resistance. Methods: In our study, we presented a bladder cancer patient who had been a bona fide responder to first-line gemcitabine plus cisplatin regimen and second-line pazopanib (tyrosine kinase inhibitor (TKI) for FGFR3-TACC3 fusion) but finally had disease progression as an ideal case for showing genomic alteration during drug resistance. We applied whole-exome sequencing and ultra-deep target sequencing to the patient pre- and post- pazopanib resistance. Protein-protein interaction (PPI) network and Gene Ontology (GO) analyses were used to analysis protein interactions and genomic alterations. Patient-derived xenograft (PDX) model was built to test drug sensitivity. Results: Twelve mutations scattered in 12 genes were identified by WES pre- pazopanib resistance, while 63 mutations in 50 genes arose post- pazopanib resistance. PPI network showed proteins from multiple epigenetic regulator families were involved post- pazopanib resistance, including subunits of chromatin remodeler SWI/SNF complex ARID1A/1B and SMARCA4, histone acetylation writers CREBBP, histone methylation writer NSD1 and erasers KDM6A/5A. GO enrichment analysis showed pazopanib resistance genes were prominently tagged for chromatin modification, transcription, as well as gland development, leaving genes with the best adaptive FGFR TKI-coping mechanisms. In addition, significantly elevated tumor mutational burden suggested possible utility of immunotherapy. Intriguingly, PDX model suggested that, sensitivity to original chemotherapy regimen (cisplatin) was restored in patient tumor post-pazopanib. (Continued on next page)
* Correspondence: [email protected] † Zhou Tong and Cong Yan contributed equally to this work. 1 Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwi
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