Abstract 749: Both amplification and protein expression are required to predict FGFR tyrosine kinase inhibitor sensitivity in lung cancer

Abstract

Abstract FGFR1 amplification has been suggested to be a driver oncogene in squamous and small cell lung carcinoma. However, early clinical trials show that response rate of FGFR tyrosine kinase inhibitors (FGFR-TKIs) is 20-30% in patients with FGFR1 amplified lung cancer. To elucidate the reason for de novo resistance to FGFR-TKI, six FGFR1 amplified lung cancer cell lines (NCI-H1581, DMS-114, NCI-H520, NCI-H1703, HCC95, and Calu-3) were analyzed. These cells were confirmed to have FGFR1 amplification by FISH analysis. Cell viability assay showed only 2 of six cell lines, NCI-H1581 and DMS-114, are sensitive to a FGFR-TKI, BGJ-398. Among BGJ-398 insensitive cells, NCI-H1703, HCC95, and Calu-3 cells express low mRNA and protein level of FGFR1 even in the presence of FGFR1 amplification. In addition, while BGJ-398 downregulates ERK phosphorylation in FGFR1 protein expressing cells, the drug had no effect on ERK signaling in BGJ-398 resistant cells with low FGFR1 protein expression. Importantly, other driver oncogenes were found in these BGJ-398 insensitive cell lines. PDGFRa amplification in H1703 cells and HER2 amplification in Calu-3 cells were reported previously. In this study, we have also found ERBB3 ligand NRG1 was overexpressed in HCC95 cells. Knockdown of NRG1 suppressed cell growth and combination of lapatinib with BGJ-398 led to cell death. To further determine whether FGFR1 protein expression is enough for the sensitivity to FGFR-TKIs, lung cancer cell lines were screened to FGFR-TKIs, BGJ-398 and PD-173034. This screen identified that all FGFR-TKI sensitive cell lines harbor FGFR1 amplification with high protein expression. These results suggest FGFR-TKIs should be used to patients harboring both FGFR1 amplification and protein expression. In case tumors with FGFR1 amplification, but expressing low FGFR1 protein, another driver oncogene may coexist and targeting both FGFR1 and these coexisting driver oncogenes are required to treat these tumors. Citation Format: Hiromichi Ebi, Hiroshi Kotani, Seiji Yano. Both amplification and protein expression are required to predict FGFR tyrosine kinase inhibitor sensitivity in lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 749. doi:10.1158/1538-7445.AM2015-749