Abstract LB_B08: The SRG OncoRat supports tumors derived from several RAS mutant cell lines for pre-clinical testing of RAS-inhibitors

Abstract

Abstract RAS family proteins have emerged as important molecular targets in multiple cancer therapeutics due to their role in hypertrophic and pro-mitotic signaling. KRAS is a small GTPase that is activated in response to growth factors including HGF, TGFα, and EGF. KRAS then activates the MAP kinase (MAPK; RAF/MEK/ERK) signaling pathway, driving ERK translocation to the nucleus, and resulting in transcription of pro-mitotic and hypertrophic genes. Furthermore, KRAS contributes to PI3K/AKT/mTOR signaling, leading to transcriptional activation as well as protein synthesis via mTOR. We validated several RAS mutant cell-derived tumor xenograft models in the SRG OncoRat. Cells were inoculated subcutaneously in the flank of SRG rats. To date, we have validated tumor growth using the HT-1080 fibrosarcoma NRAS mutant (Gln61Lys (c.181C>A)) cell line. We have also validated a suite of KRAS mutant lines in the SRG OncoRat, including: A-549 lung adenocarcinoma (Gly12Ser (c.34G>A)); NCI-H2122 NSCLC adenocarcinoma (Gly12Cys (c.34G>T)); MIA PaCa-2 pancreatic ductal adenocarcinoma and H-358 NSCLC adenocarcinoma (Gly12Cys (c.34G>T)); Capan-2 pancreatic ductal adenocarcinoma (Gly12Val (c.35G>T)); NCI-H441 NSCLC papillary adenocarcinoma (Gly12Val (c.35G>T)); NCI-H1734 NSCLC adenocarcinoma (Gly13Cys (c.37G>T)); and MDA-MB-231 breast adenocarcinoma (Gly13Asp (c.38G>A)). All cell lines showed robust and consistent tumor growth when injected subcutaneously into the SRG OncoRat. These models provide valuable tools for pre-clinical testing of RAS inhibition. Citation Format: Grace Walton, Diane Begemann, Cynthia Dunn, Valeriya Steffey, Christopher Brenzel, Fallon Noto. The SRG OncoRat supports tumors derived from several RAS mutant cell lines for pre-clinical testing of RAS-inhibitors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_B08.