Supplementary Fig. S1. Generation of patient-derived xenografts from surgery and biopsy specimens of non small cell lung cancer Supplementary Fig. S2. Squamous cell carcinoma patient-derived xenografts recapitulate the genomic phenotype of patients'' tumors Supplementary Fig. S3. Analysis of biomarkers of response to FGFR inhibition Supplementary Fig. S4. High FGFR1 RNA expression does not predict patient outcome Supplementary Fig. S5. PIK3CA amplification does not predict response to PI3K inhibitors Supplementary Fig. S6. FGFR targeted therapy in FGFR inhibitor resistant tumors does not increase cisplatin sensitivity
ARTICLE ABSTRACT
Lung squamous cell carcinoma (SqCC) is a molecularly complex and genomically unstable disease. No targeted therapy is currently approved for lung SqCC, although potential oncogenic drivers of SqCC have been identified, including amplification of the fibroblast growth factor receptor 1 (FGFR1). Reports from a recently completed clinical trial indicate low response rates in patients treated with FGFR tyrosine kinase inhibitors, suggesting inadequacy of FGFR1 amplification as a biomarker of response, or the need for combination treatment. We aimed to develop accurate models of lung SqCC and determine improved targeted therapies for these tumors. We show that detection of FGFR1 mRNA by RNA in situ hybridization is a better predictor of response to FGFR inhibition than FGFR1 gene amplification using clinically relevant patient-derived xenograft (PDX) models of lung SqCC. FGFR1-overexpressing tumors were observed in all histologic subtypes of non–small cell lung cancers (NSCLC) as assessed on a tissue microarray, indicating a broader range of tumors that may respond to FGFR inhibitors. In FGFR1-overexpressing PDX tumors, we observed increased differentiation and reduced proliferation following FGFR inhibition. Combination therapy with cisplatin was able to increase tumor cell death, and dramatically prolonged animal survival compared to single-agent treatment. Our data suggest that FGFR tyrosine kinase inhibitors can benefit NSCLC patients with FGFR1-overexpressing tumors and provides a rationale for clinical trials combining cisplatin with FGFR inhibitors. Mol Cancer Ther; 16(8); 1610–22. ©2017 AACR.
