Transbronchoscopic patient biopsy-derived xenografts as a preclinical model to explore chemorefractory-associated pathways and biomarkers for small-cell lung cancer. (January 2019)

• Record Type: Journal Article
• Authors: Wang, Zhijie; Fu, Shuai; Zhao, Jun; Zhao, Wei; Shen, Zhirong; Wang, Di; Duan, Jianchun; Bai, Hua; Wan, Rui; Yu, Jiangyong; Wang, Shuhang; Chen, Hanxiao; Chen, Bolu; Wang, Lai; Wang, Jie
• Is Part Of: Cancer letters. Volume 440-441(2019)
• Page Start: 180
• Page End: 188
• Publication Date: 2019-01
• Subjects: Transbronchoscopic patient biopsy-derived xenografts -- Chemorefractory -- Small-cell lung cancer -- Mitogen-activated protein kinase -- Receptor tyrosine kinase; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2018.10.014
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Insufficient tumor tissue is a major barrier for cancer biology research in small-cell lung cancer (SCLC) and has driven the development of patient-derived xenografts (PDXs) from biopsy tumor tissues. Here, we utilized transbronchoscopic biopsy specimens from SCLC tumors to establish PDXs and evaluated the genomic profile using next-generation sequencing and an RNA sequencing platform. The PDX establishment rate was 54.1% (40/74). PDXs largely recapitulated the major characteristics of their corresponding primary tumors, such as histopathology, genetic profile, and chemo-responsiveness. Compared with chemosensitive (chemo-S) PDXs, chemorefractory (chemo-R) PDXs demonstrated significant gene aberrances in the mitogen-activated protein kinase (MAPK) pathway and a higher frequency of receptor tyrosine kinase (RTK)-related genes. Phosphorylated ERK (pERK) was associated with chemo-R status. Patients with positive pERK expression demonstrated significantly inferior progression-free survival after first-line chemotherapy compared with that of patients who were negative for pERK ( p < 0.001). Collectively, transbronchoscopic biopsy SCLC PDXs can serve as a model for genomic profiling and identifying biomarkers predictive of chemo-R status. Using PDXs, RTK-related gene aberrances and pERK expression were found to be associated with chemo-R SCLC. Highlights: Patient derived xenografts (PDXs) can be established through transbronchoscopic biopsy of small-cell lung cancers (SCLC). Transbronchoscopic biopsy SCLC PDXs can serve as a model for mechanism exploration of chemo-refractory responses. Transbronchoscopic biopsy SCLC PDXs can be used for depicting the genomic profiling of SCLCs. Receptor tyrosine kinase related gene aberrances and pERK could potentially predict chemo- refractory status.