Abstract 2156: Lung niche factors for progenitor cell self-renewal sustain lung cancer stem cells and contribute to drug resistance to kinase inhibitors in non-small cell lung cancer

Abstract

Abstract A mechanism underlying anti-cancer drug resistance relies on the existence of cancer stem cells (CSCs). However, CSCs are either absent or are few in number in xenograft tumors and syngeneic mouse models. We developed new lung cancer mouse models with CSCs to elucidate the role of CSCs in resistance to targeted therapeutics in non-small cell lung cancer (NSCLC). Mouse lung organoids containing progenitor cells were cultured in complete medium containing lung niche factors, FGF-10 and HGF, and were infected with a retrovirus encoding a Kras mutation (G12D), an Egfr deletion, and the EML4-ALK fusion protein. These induced CSCs were transplanted into mice, and the established tumors were cultured in vitro to test for drug sensitivity to trametinib, erlotinib, and crizotinib in the presence or absence of niche factors. The tumors that were poorly differentiated contained EpCAM-, Cd49f-, and Sca-1-positive CSCs. These mouse models allowed the prediction of clinical responses to targeted therapeutics, i.e., the tumor cells with the Egfr deletion and those with EML4-ALK fusion proteins showed strong responses to erlotinib and crizotinib, respectively. In addition, we found that Kras mutant cancer cells were resistant to trametinib due to activation of the HGF/Met pathway since HGF is an essential niche factor for lung progenitor cell proliferation. Combination treatment with trametinib and a Met inhibitor showed a synergistic effect in Kras mutant tumors. Based on these results, we propose a treatment approach that focuses on the use of niche factors for lung progenitor cells in NSCLC. Citation Format: Akinori Mitsui, Sachiko Yokokawa, Osamu Nagano, Hideyuki Saya. Lung niche factors for progenitor cell self-renewal sustain lung cancer stem cells and contribute to drug resistance to kinase inhibitors in non-small cell lung cancer [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 2156.