Abstract 1160: The novel osimertinib resistant lung cancer mice model harboring EGFR mutations driven by the SP-C promoter
Authors: Kadoaki Ohashi, Hisao Higo, Go Makimoto, Kenichiro Kudo, Kazuya Nishii, Kiichiro Ninomiya, Hiroe Kayatani, Takashi Ninomiya, Toshio Kubo, Kammei Rai, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Katsuyuki Kiura
Journal: Cancer Research (2018)

Abstract Background: Discovery of driver mutations has drastically changed clinical practice in patients with lung tumors. Management of lung tumors with appropriated oncoprotein inhibitors is a key for longer survival. Osimertinib is an irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) and the new compound changed the standard treatment for non-small-cell lung cancer (NSCLC) harboring EGFR T790M. We previously established two strains of transgenic lung cancer mice model harboring mice Egfr ex19 deletion(mDEL) or human EGFR L858R(hLR) driven by an SP-C promoter (Ohashi Cancer sci 2008, Ohashi Cancer res 2009). The mice develop EGFR dependent lung adenocarcinoma multifocally, so it detaches to clinical primary lung cancers which usually occur mono-focally. In addition, the tumors develop from type II pneumocyte one after another. The more clinically relevant lung cancer mice model is warranted. Material and Methods: The lung tumors from each of transgenic mice, mDEL or hLR, were transplanted subcutaneously into C57BL/6J mice. The each of engrafted tumors was able to be serially transplanted and grew in subcutaneous of other C57BL/6J mice. In addition, the tumor engraftment was succeeded in peritoneum by intraperitoneal administration or lung by tail vein injection. Gefitinib (50mg/kg) or Osimertinib (5 or 15 mg/kg) were orally administrated. Results These tumors maintained the EGFR dependency in novel syngenic xenograft models, thus EGFR-TKI, gefitinib inhibited the tumor growth significantly. However, same as human lung tumors, these tumors eventually acquired resistance and re-grew. mDEL tumors got the resistance for five months and hLR tumors acquired the resistance for two months after gefitinib treatment. Interestingly secondary mutation Egfr T790I on mDEL tumors and secondary mutation EGFR T790M on hLR tumors were detected. Strikingly, third-generation EGFR-TKI, osimertinib inhibited the tumor growth in vivo in each of gefitinib-resistant tumors harboring secondary mutations in vivo. Resembling human lung cancer, these tumors again acquired the resistance to osimertinib and re-grew two months after of treatment with osimertinib. The resistant mechanisms are under investigation. Conclusion: We established clinically relevant novel EGFR-TKI resistant mice model. The strength of the model is 1) syngenic model, 2) the mice have a normal immune system and 3) the model presented a clinically relevant resistant mechanism. We are assessing an alternative treatment including combination therapies or immunotherapy in this mice model. (This work was supported by KAKEN 16K19454, KAKEN 15H04830) Citation Format: Kadoaki Ohashi, Hisao Higo, Go Makimoto, Kenichiro Kudo, Kazuya Nishii, Kiichiro Ninomiya, Hiroe Kayatani, Takashi Ninomiya, Toshio Kubo, Kammei Rai, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Katsuyuki Kiura. The novel osimertinib resistant lung cancer mice model harboring EGFR mutations driven by the SP-C promoter [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1160.