Background: Brain metastasis is a formidable challenge in lung cancer treatment. The incidence has been increasing recently because of the advances of treatment which leads to prolonged survival of many patients.

Methods: We established xenograft model of brain metastasis. Repeated rounds of in vivo selection and ex vivo primary cultures of the brain metastases resulted in a cell line with a high propensity to metastasize to the brain. Brain-tropism was confirmed by bioluminescence study. Gene expression profiles between parental lung cancer cells (PC9) and brain-tropic cells (PC9-Br) was compared by Agilent Gene Expression Microarray followed by Ingenuity Pathway Analysis. The biologic effects and clinical implications of the candidate molecules were further investigated.

Results: Significant activation of IGF and WNT signaling pathways was detected in PC9-Br, as compared with the parental cells. We selected IGF pathway as the first step to explore the potential therapeutic implication. Western blot and RT-PCR validated the results of IGF2 overexpression and activated IGF1R (pIGF1R) in PC9-Br cells. In vitro drug sensitivity tests showed that PC9-Br, in comparison to parental cells, was more resistant to erlotinib, an EGFR TKI (IC50: 30nM for PC9 and 189nM for PC9-Br). Knocking down IGF2 expression in PC9-Br reversed the drug resistance, while adding IGF2 to PC9 enhanced the resistance. In clinical samples, there was a significantly higher expression of pIGF1R in 26 brain metastases as compared to their paired primary lung tumors (mean of H score differences=40.96, 95% C.I.=10.96∼70.96, P=0.0094).

Conclusions: IGF signaling pathway is activated in brain-tropic lung cancer cells and could potentially be a therapeutic target for brain metastasis.

Acknowledgement: This study was supported by Research Grant 101-M2002 from the National Taiwan University Hospital.

Citation Format: Pei-Fang Wu, Ching-Hung Lin, Wen-Chang Huang, Wen-Chi Feng, Yen-Shen Lu, Chih-Hsin Yang, Ann-Lii Cheng. Activated insulin-like growth factor (IGF) signaling pathway is a potential therapeutic target for brain metastasis from lung cancer. [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 3886. doi:10.1158/1538-7445.AM2013-3886