Abstract 28: In vivoscreening platform based on Ba</>F3 kinase engineered cell lines for discovery of next-generation kinase inhibitors

Abstract

Abstract Protein kinases have become very popular targets for cancer and other diseases therapy, with more than 70 kinase inhibitor drugs approved by FDA since 2001. Due to innate or acquired drug resistance of tumors, most of these small-molecule inhibitors can only delay tumor progression. Next-generation kinase inhibitors with better specificity and lower drug resistance remain to be developed. Ba/F3 is a mouse pro-B cell line which is dependent on IL-3 for survival and proliferation. Upon transduction of a driver gene such as kinase genes or their mutants, Ba/F3 cells switch from IL3-dependent to driver gene-dependent, which makes Ba/F3 cells a powerful tool for the discovery of new kinase inhibitors. Our group has constructed more than 500 Ba/F3 engineered cell lines stably transfected with mutants of kinase genes. These Ba/F3 kinase cell lines are well validated by sequencing, western blot and inhibitor test, and cover many hot kinases, including EGFR (151 cell lines), FGFR (45 cell lines), ERBB2 (38 cell lines), KRAS (36 cell lines), BCR-ABL (36 cell lines), EML4-ALK (33 cell lines), KIF5B-RET (30 cell lines), FLT3 (26 cell lines) et.al. Most of these transformed Ba/F3 cell lines can be used in allograft models in immune-deficient mice. Based on these Ba/F3 kinase cell line allograft models, we established an in vivo screening platform to evaluate the efficacy and toxicity of drug candidatestargeting specific mutant types of kinases, as well as comparisons with previous generation drugs. Overall, our data indicate that Ba/F3 kinase cell line-derived allograft models are a powerful model for the discovery of next-generation kinase inhibitors. Citation Format: Tongtong Liu, Feng He, Xuyang Duan, shuliang Li, Chang Liu, Jinying Ning, Feng Hao. In vivoscreening platform based on Ba</>F3 kinase engineered cell lines for discovery of next-generation kinase inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 28.