Australian researchers have discovered a better biomarker for identifying which patients with lung squamous cell carcinoma will respond to fibroblast growth factor receptor (FGFR) inhibitors.
The study using patient-derived xenografts in laboratory models of the disease, found high levels of FGFR1 in tumour RNA were a better predictor of response to FGFR tyrosine kinase inhibitors than the current test of FGFR1 amplification.
They also found that combining FGFR inhibition with cisplatin increased tumour cell death and prolonged survival in the animal model.
The limbic spoke to Walter and Eliza Hall Institute researcher Dr Clare Weeden about the study.
Why are you targeting FGFR1?
Lung adenocarcinomas have epidermal growth factor receptor (EGFR) mutations and targeted EGFR inhibitors have been approved since about 2004 but there is no such targeted therapy for lung squamous cell carcinomas. FGFR1 is over-expressed in lung squamous cell carcinomas and the efficacy of EGFR inhibitors suggested the strategy of targeting FGFR1 could work for these cancers.
It is very important to find a biomarker that can be used to recruit candidates into clinical trials and predict their response to treatment. FGFR1 amplification was detected in about 22% of lung squamous cell carcinomas and it was thought it must be a driver of cancer growth. Tests in cell lines showed FGFR1 amplification predicted response to the drugs.
How does your research using patient-derived xenografts change that thinking?
There is a limit to what cell lines can explain in pre-clinical tests. We used a more complex model known as patient-derived xenografts that mimics patients’ cancers. In our study, gene amplification – too many copies of the FGFR1 gene – did not predict response to FGFR inhibitor therapy.
However FGFR1 RNA expression was a better predictor of response. The study also found high FGFR1 RNA expression in other lung cancer subtypes including adenocarcinomas and large cell carcinomas.
What needs to come next in translating this knowledge into clinical practice?
I think the most important finding is that FGFR1 RNA expression better predicts response to FGFR inhibition in lung squamous cell carcinoma. We need to test whether other subtypes of lung cancer with high FGFR1 RNA will also respond to the drug.
Our study was also the first to show that FGFR inhibition can stop the growth signal to the cancer cell but in combination with cisplatin, the two treatments synergise to enhance cancer cell death resulting in prolonged survival. Our research shows combining FGFR inhibitors with chemotherapy should be looked at in future clinical trials.