Abstract 5597: Genomic profiling of syngeneic mouse cell lines and in vitro screen of the models against checkpoint inhibitors and target agents for preclinical application

Abstract

Abstract Cancer immunotherapy has provided substantial clinical benefit in a significant number of patients with advanced diseases. In pre-clinical studies, CrownBio has developed a large collection of syngeneic models to facilitate in vivo efficacy testing of immune-oncology agents in mice (MuScreenTM). To combine the ostensibly separate therapeutic strategies of activating immune cells against and targeting the unique genetic characteristics of a tumor model, we sought to thoroughly characterize the mutation profiles of these syngeneic mouse cell lines and examine drug response profiles of these cell line models. The goal of this work was to provide an in vitro system in evaluating combination effectiveness when targeting both immune checkpoint markers and oncogenic targets in preclinical studies. To this end, we investigated mutation and gene expression profiles of 18 mouse cancer cell lines out of the panel of 23 syngeneic mouse models included in the MuScreenTM for 50 well defined cancer-related mutations among 30,690 variants in exonic regions called by RNAseq (Illumina HiSeq X10). The somatic mutations revealed through the bioinformatics analysis include ALK (3 - frequency, same for the rest), BRAF (4), BRCA1 (7), BRCA2 (12), EGFR (3), ERBB2 (6), EGFR3 (2), FBXW7 (10), FLT3 (12), HRAS (1), KRAS (8), NRAS (1), PDGFRA (11), PTCH1 (9), PIK3CA (2), PTEN (6), RET (3), SETD2 (5), SMAD4 (3), SMO (13), TRP53 (13), TSC1 (3), and TSC2 (10). All of these oncogenic alterations are clinically actionable (Cancer Discovery 2, 82-93, 2012). The same set of genes was also subject to mRNA expression change analysis. We screened the 18 mouse cell lines with a few selected target therapy agents, and performed combination assays of these agents together with check point inhibitors such as aPD1, aPDL1, in a co-culture system with mouse T cells. An IncuCyte real-time imaging platform was used to distinguish activities on T cells and tumor cells. The results and the implications will be discussed. Citation Format: Frank Xing, Wubin Qian, Chunlan Dong, Xiaoxi Xu, Sheng Guo, Qian Shi. Genomic profiling of syngeneic mouse cell lines and in vitro screen of the models against checkpoint inhibitors and target agents for preclinical application [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5597. doi:10.1158/1538-7445.AM2017-5597