Identification and Characterization of the Molecular Mechanisms of SCLC Chemo-Radiation Resistance

Abstract

Small cell lung cancer (SCLC) is among the most aggressive form of lung malignancies and accounts for 15-20% of all lung cancers. It has the tendency to metastasize early, thus limited-stage SCLC patients still receive systemic treatment with chemo-radiotherapy (chemoXRT) for their localized disease. SCLC is exceptionally sensitive to chemoXRT and exhibits high response rates; however, the recurrence rate is > 80% and patients relapse with tumors that resist further treatments. Elucidating mechanisms of chemoXRT resistance in SCLC is needed to develop improved therapies and positively impact patient outcomes.To better interrogate mechanisms of chemoXRT resistance, we developed a SCLC patient-derived xenograft (PDX) in vivo system for the major molecular subtypes of SCLC (classic and variant). We also established a novel PDX organoid (PDO) model to study the molecular underpinnings of chemoXRT resistance in SCLC.PDX tumor bearing mice were treated with: 1) vehicle control; 2) cisplatin plus etoposide (EP); 3) radiotherapy (XRT); and 4) both EP/XRT. A major response was observed within the EP/XRT arm compared to vehicle or single therapy arms. Whole transcriptome profiling among all treatment arms revealed molecular pathways and biological processes associated with chemoXRT resistance. By comparing our data with two previous SCLC patient cohort studies, we identified gene candidates for functional validation of chemoXRT resistance (i.e., ST6GAL1, TNIK and SOHLH2). To enable real-time cellular and molecular analysis of PDX behavior ex vivo and to validate SCLC chemoXRT resistance candidate genes, classic and variant SCLC organoids will be used. PDOs can be cultured up to 30 days in medium and parental PDX molecular subtype phenotypes are maintained as shown by comparative genomic hybridization, RNA-seq and protein marker analyses. Additionally, PDOs are capable of forming tumors in vivo.Genetically manipulated SCLC PDOs will be utilized as a tool to identify and validate candidates for chemoXRT resistance to be used as biomarkers and targets to combat chemoXRT resistance in SCLC.