Abstract 4309: Establishment of intratumor heterogeneity using patient derived lung cancer cells

Abstract

Abstract Overcoming cancer treatment resistance is a problem that must be solved to improve the prognosis of cancer patients. In recent years, genome analysis has revealed the existence of multiple subgroups with different properties within a single tumor, and intratumor heterogeneity is a cause of treatment resistance. It has also been reported that. However, the mechanism of intratumor heterogeneity remains unclear. Previous research on intratumor heterogeneity has mainly focused on analyzing patient cancer cells, classifying subgroups, and estimating characteristic factors. This method has two drawbacks. One is limitations in including all subgroups as research subjects, and other is lack of verification of whether characteristic factors are actually involved in intratumor heterogeneity in patients. Therefore, it is necessary to use a model of "early intratumor heterogeneity" in which monoclonal cells are divided into subgroups with different properties, and to verify the discovered factors using patient-derived cancer cell lines. In alectinib-resistant cell line (H2228-AR1S) created from monoclonal ALK-positive lung cancer cell line (H2228) by exposing to alectinib in vitro, existence of two fractions with different appearances. Using flow cytometry, it was revealed that H2228-AR1S bimodally expresses EpCAM, and the EpCAM-low fraction has high migration ability. In EpCAM-low fraction, epithelial markers were decreased, and mesenchymal markers were increased using immunoblotting. It suggests that EpCAM low subpopulation has undergone epithelial-mesenchymal transition (EMT). Additionally, we established a BRAF-positive lung cancer cell line (KTOR83) collected with consent from patients attending Kyoto University Hospital. Cells after in vitro dabrafenib exposure to KTOR83 showed bimodal EpCAM expression, and the EpCAM-low fraction has high migration ability. We established an intratumor heterogeneous model using commercially available cells and a patient-derived lung cancer cell line. Furthermore, we will explore factors common to the two models and examine factors involved in intratumor heterogeneity. Citation Format: Tomoko Funazo, Hiroaki Ozasa, Takahiro Tsuji, Yusuke Shima, Keiichiro Suminaga, Kentaro Hashimoto, Hiroshi Yoshida, Tatsuya Ogimoto, Kazutaka Hosoya, Hitomi Ajimizu, Takashi Nomizo, Hironori Yoshida, Toyohiro Hirai. Establishment of intratumor heterogeneity using patient derived lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4309.