Abstract 1118: Engineered cell line panel complemented with in vivo models to enable next-generation target therapy discovery in cancer

Many cancer types are driven by specific gene aberrances, like gene fusions, mutations and copy number changes. It has led to the successful application of a number of target therapeutics, of which kinase inhibitors represent a good example. However, acquired resistance is almost inevitable at the end of any target therapy treatment, which makes it urgent a need to discover new-generation therapeutics. There are strong evidences suggesting acquired resistance should be largely attributed to certain secondary mutations, such as EGFRT790M, RETV804L and BTKC481S. At discovery stage it is critical to generate preclinical cancer models harboring these specific gene aberrances both in vitro and in vivo. Biopsy from patient with clinical resistance could be an optional starting point. But it is much more straightforward and efficient if these well-studied gene aberrance could be constructed and engineered into host cell lines directly. The transformed cell line can further be inoculated into host mice to make in vivo test feasible. Here we are reporting the establishment of a panel of engineered BaF3 cell lines for a series of cancer driver gene aberrances against EGFR, RET, ROS1, BTK and FLT3. Taking RET as example, we constructed the activating gene fusion of KIF5B-RET, along with its mutated versions, KIF5B-RETV804L and KIF5B-RETV804M. These 3 constructs were transfected into BaF3 cell line, respectively. After rounds of in vitro selection, the stable BaF3 cell line harboring KIF5B-RETWT, KIF5B-RETV804L or KIF5B-RETV804M was subjected into in vitro test of three multiple kinase inhibitors with RET inhibitory activity, including Ponatinib, Sunitinib and Sorafenib. Consistent to other reports, Ponatinib was demonstrated superior to the other two RET inhibitors when suppressing the two V804 mutated cell line growths. The in vivo growth of these cell lines have also been confirmed in house. Beyond these five target genes, we have been working on other driver genes to expand the panel scope continuously. HER2 exon20 ins, PDGFRaT674I and KITT670I models are already under development, while many others are on our radar. In summary, our ever-expanding panel of engineered cell lines complemented with in vivo models represents valuable assets to empower the discovery of next-generation target therapeutics against cancer. Citation Format: Zhixiang Zhang, Xiaohe Shi, Xiangyang Zuo, Qingyang Gu, Qunsheng Ji. Engineered cell line panel complemented with in vivo models to enable next-generation target therapy discovery in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1118.