journal contribution
posted on 2023-04-03, 15:46 authored by Clare E. Weeden, Aliaksei Z. Holik, Richard J. Young, Stephen B. Ma, Jean-Marc Garnier, Stephen B. Fox, Phillip Antippa, Louis B. Irving, Daniel P. Steinfort, Gavin M. Wright, Prudence A. Russell, Matthew E. Ritchie, Christopher J. Burns, Benjamin Solomon, Marie-Liesse Asselin-Labat <p>Supplementary Table 1. Engraftment rates of lung cancer patient-derived xenografts vary according to histology and specimen type; Supplementary Table 3. TP53 mutations in primary lung cancer and corresponding PDX, as detected by exome sequencing; Supplementary Table 4. FGFR1 FISH scores are conserved for successive passages of squamous cell carcinoma PDXs 792, 406, 788, and 926; Supplementary Table 5. FGFR1 gene amplification does not always correlate with FGFR1 RNA expression in a tissue microarray patient cohort; Supplementary Table 6. FGFR1 gene amplification does not always correlate with FGFR1 RNA expression in squamous cell carcinoma patients from a tissue microarray cohort; Supplementary Table 7. FGFR1 gene amplification does not always correlate with RNA expression in a squamous cell carcinoma PDX cohort; Supplementary Material and Methods, and Supplementary Figure Legends</p>
Funding
Viertel Foundation Senior Medical Researcher Fellowship
Victorian Cancer Agency
History
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.
