Abstract 4468: Cripto-1 Elicits Innate Resistance to EGFR Inhibitors in Non-Small Cell Lung Cancer Harboring EGFR-sensitizing Mutations.

Abstract Non-small cell lung cancer (NSCLC) carrying sensitizing epidermal growth factor receptor (EGFR) mutations can initially benefit from erlotinib (EGFR inhibitor) treatment. However, patients invariably develop resistance through secondary EGFR mutations, c-MET amplification, epithelial-mesenchymal transition (EMT), small cell lung cancer transformation, PIK3CA mutation and other unknown mechanisms. Here we examined whether Cripto1, which has been shown to induce EMT, could cause erlotinib resistance. We show that innate erlotinib-resistant lung adenocarcinomas carrying sensitizing EGFR mutations exhibit higher level of Cripto1 expression than their erlotinib sensitive counterparts. Ectopic expression of Cripto1 rendered erlotinib-sensitive lung adenocarcinoma cells resistant to erlotinib both in vitro and in a xenograft model. Moreover, Cripto1 activated Zeb1/EMT signaling pathway in EGFR-TKI resistant cells. High Cripto1 expression correlated with poor prognosis of NSCLC patients. Our study provides a novel Cripto1-dependent mechanism of EGFR-TKI resistance that may pave the way for the development of therapies to overcome EGFR-TKI resistance in lung cancer patients. Citation Format: Kang-Seo Park, Giaccone Giuseppe, Yisong Wang, Trung Pham, Yongwha Moon, Ji Luo, Liam Changwoo Lee, Tetsuya Mitsudomi, Isamu Okamoto, Yasushi Yatabe, Tony Mok, Mark Raffeld, Liqiang Xi, David S. Salomon, Caterina Bianco. Cripto-1 elicits innate resistance to EGFR inhibitors in non-small cell lung cancer harboring EGFR-sensitizing mutations. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4468. doi:10.1158/1538-7445.AM2013-4468