Clinical application of a lung cancer organoid (tumoroid) culture system
Etsuko Yokota, Miki Iwai, Takuro Yukawa, M. Yoshida, Yoshio Naomoto, Minoru Haisa, Yasumasa Monobe, Nagio Takigawa, Minzhe Guo, Yutaka Maeda, Takuya Fukazawa, Tomoki Yamatsuji
Abstract
Abstract Despite high expectations for lung tumoroids, they have not been applied in the clinic due to the difficulty of their long-term culture. Here, however, using AO (airway organoid) media developed by the Clevers laboratory, we succeeded in generating 3 lung tumoroid lines for long-term culture (>13 months) from 41 lung cancer cases (primary or metastatic). Use of nutlin-3a was key to selecting lung tumoroids that harbor mutant p53 in order to eliminate normal lung epithelial organoids. Next-generation sequencing (NGS) analysis indicated that each lung tumoroid carried BRAF G469A , TPM3-ROS1 or EGFR L858R /RB1 E737* , respectively. Targeted therapies using small molecule drugs (trametinib/erlotinib for BRAF G469A , crizotinib/entrectinib for TPM3-ROS1 and ABT-263/YM-155 for EGFR L858R /RB1 E737* ) significantly suppressed the growth of each lung tumoroid line. AO media was superior to 3 different media developed by other laboratories. Our experience indicates that long-term lung tumoroid culture is feasible, allowing us to identify NGS-based therapeutic targets and determine the responsiveness to corresponding small molecule drugs.