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Updated: Feb 28, 2026
Author Spotlight: Establishing a Murine Non-Small Cell Lung Cancer Model for Developing Nanoformulations of Anticancer Drugs
Published on: May 10, 2024
Cisplatin Increases Sensitivity to FGFR Inhibition in Patient-Derived Xenograft Models of Lung Squamous Cell
Clare E Weeden1,2, Aliaksei Z Holik1,2, Richard J Young3
1ACRF Stem Cells and Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
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.
Insights
Fibroblast growth factor receptor 1 (FGFR1) mRNA expression, not gene amplification, predicts response to FGFR inhibitors in lung squamous cell carcinoma. Combination therapy with cisplatin enhances efficacy.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Lung squamous cell carcinoma (SqCC) is a complex cancer lacking approved targeted therapies.
- Fibroblast growth factor receptor 1 (FGFR1) amplification is a potential driver, but clinical trials show limited response to FGFR inhibitors.
- Current biomarkers like FGFR1 gene amplification may be inadequate for predicting treatment response.
Purpose of the Study:
- To develop accurate models for lung SqCC.
- To identify improved targeted therapies for lung SqCC.
- To evaluate FGFR1 mRNA as a predictive biomarker for FGFR inhibition.
Main Methods:
- Utilized patient-derived xenograft (PDX) models of lung SqCC.
- Assessed FGFR1 gene amplification and FGFR1 mRNA expression via RNA in situ hybridization.
- Evaluated FGFR inhibition and combination therapy with cisplatin in PDX models.
- Analyzed FGFR1 overexpression across non-small cell lung cancer (NSCLC) subtypes using tissue microarrays.
Main Results:
- FGFR1 mRNA detection is a superior predictor of response to FGFR inhibition compared to FGFR1 gene amplification.
- FGFR1 overexpression is present across various NSCLC histologic subtypes.
- FGFR inhibition in FGFR1-overexpressing tumors led to increased differentiation and reduced proliferation.
- Combination therapy with cisplatin significantly enhanced tumor cell death and prolonged survival in PDX models.
Conclusions:
- FGFR tyrosine kinase inhibitors show potential benefit for NSCLC patients with FGFR1-overexpressing tumors.
- FGFR1 mRNA expression is a promising biomarker for patient selection.
- Clinical trials combining cisplatin with FGFR inhibitors are warranted for NSCLC treatment.
