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

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.

Keywords: Chemorefractory; Mitogen-activated protein kinase; Receptor tyrosine kinase; Small-cell lung cancer; Transbronchoscopic patient biopsy-derived xenografts.