FGFR1 promotes the stem cell-like phenotype of FGFR1-amplified non-small cell lung cancer cells through the Hedgehog pathway

// Wenxiang Ji 1, 2 , Yongfeng Yu 1 , Ziming Li 1 , Guan Wang 3 , Fan Li 2 , Weiliang Xia 2 , Shun Lu 1 1 Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China 2 State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China 3 Genomics Center, WuXiAppTec Co., Ltd., Shanghai 200131, China Correspondence to: Weiliang Xia, e-mail: wlxia@sjtu.edu.cn Shun Lu, e-mail: shun_lu@hotmail.com Keywords: FGFR1, GLI2, lung squamous cell cancer, stem cell-like phenotype Received: August 22, 2015     Accepted: January 29, 2016     Published: February 25, 2016 ABSTRACT Cancer stem cell-like phenotype is critical for tumor formation and treatment resistance. FGFR1 is found to be amplified in non-small cell lung cancer, particularly in the lung squamous cell cancer (LSCC). Whether FGFR1 contributes to the maintenance of stem cell-like phenotype of FGFR1-amplified lung cancer cells remains elusive. In this study, treatment with FGFR1 inhibitor AZD4547 suppressed the growth of tumor spheres and reduced ALDH positive proportion in FGFR1-amplified lung cancer cells in vitro, as well as inhibited the growth of oncospheres and parental cells in xenograft models. Knockdown of FGFR1 recaptured the similar effect as AZD4547 in vitro. Furthermore, activation of FGFR1 and subsequently its downstream ERK signaling enhanced the expression and transcriptional activity of GLI2, which could be blocked by FGFR1 inhibitor/silencing or ERK inhibitor. Knockdown of GLI2 directly inhibited the stem-like phenotype of FGFR1-amilified cells, whereas overexpression of GLI2 sufficiently rescued the phenotype caused by FGFR1 knockdown. Notably we also identified a correlation between FGFR1 and GLI2 expressions from clinical data, as well as an inverse relationship with progression free survival (PFS). Together our study suggests that the FGFR1/GLI2 axis promotes the lung cancer stem cell-like phenotype. These results support a rational strategy of combination of FGFR1 and GLI inhibitors for treatment of FGFR1-amplified lung cancers, especially LSCC.