FGFR4 has been thoroughly described as an oncogene in many types of tumors, including colorectal and hepatocellular carcinoma. In lung adenocarcinoma, this receptor tyrosine kinase has been found to be one of the most mutated genes. Nonetheless, little work has been done to unravel its role in lung tumorigenesis so far.
Several lung cell lines, harbouring different genetic driver alterations with relevance in lung cancer, were transfected with plasmids to either overexpress or silence FGFR4. In these genetically engineered models several tumorigenic abilities were tested in vitro and in vivo. Besides, mRNA from paraffin-embedded tissue of a cohort of lung cancer patients was extracted and FGFR4 expression levels, as well as other genes found relevant, were measured and related to clinical characteristics.
FGFR4 increases oncogenic properties in SCC cell lines, but its effects in lung ADC cell lines are context-depended. This differential role of FGFR4 in tumorigenesis is due to differentially expressed genes between these two histologies in the cell lines under study, involving a molecular cooperation in some cases. The analysis of FGFR4 mRNA expression, together with the aforementioned differentially expressed genes, in a cohort of lung cancer patients, provided further support to our in vitro and in vivo results. High FGFR4 mRNA expression correlated with a shorter overall survival (OS) and progression free survival (PFS) in lung SCC patients. Nonetheless, longer OS and PFS were reported for the ADC patients with higher FGFR4 mRNA expression.
Our results show that FGFR4 oncogenic role is context-dependent and that in some cases it depends on a molecular cooperation. At a clinical level, FGFR4 mRNA expression could have a biomarker role in patient outcome. This potential prognostic role seems to be differential in the two main lung cancer histologies. The study of the molecular context of FGFR4, involving the presence of molecules with which FGFR4 is able to cooperate, could be of interest in determining the eligibility of a patient to receive FGFR-targeted therapy, or even in designing new therapeutic approaches.
Legal entity responsible for the study
CNIO-Hospital 12 Octubre
All authors have declared no conflicts of interest.