Abstract PR-008: Identification and characterization of the molecular mechanisms of SCLC chemo-radiation resistance

Abstract

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 almost 100% 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). Briefly, 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. Also, 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, we established a novel PDX organoid (PDO) model to study the molecular underpinnings of XRT resistance in SCLC. Classic and variant SCLC PDOs still retained the cellular, DNA and RNA markers consistent with their parental PDX molecular subtype classification using array comparative genomic hybridization and RNA-sequencing. We aim to utilize our novel SCLC PDX/PDO models as a tool to identify and validate candidates for chemoXRT resistance to be used as biomarkers and targets to combat chemoXRT resistance in SCLC. Citation Format: Francesca Anna Carrieri, Nick Connis, Eloise Grasset, Eddie Luidy-Imada, Andrew Ewald, Luigi Marchionni, Christine Hann, Phuoc T. Tran. Identification and characterization of the molecular mechanisms of SCLC chemo-radiation resistance [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PR-008.