Similar to EGFR another receptor tyrosine kinase
Similar to EGFR, another receptor tyrosine kinase (RTK), fibroblast growth factor receptor 4 (FGFR4), is gaining attention in the lung cancer setting. The protein expression of this receptor has been recently associated with a negative impact on lung cancer prognosis, supporting the idea that FGFR4 could have oncogenic potential in these tumors as well . Furthermore, FGFR4 has also been reported to be occasionally mutated in lung adenocarcinoma [, , ] leading to activation of oncogenic signaling pathways with impact on patient survival [18,19]. Expression of FGFR4 was found to be upregulated in EGFR-transformed mouse embryonic fibroblasts (MEFs) compared to MEFs transformed by other methods , sugesting a potential cooperative interaction between both RTKs. However, the oncogenic role of FGFR4 in the context of EGFR-dependent lung adenocarcinoma has thus far not been addressed.
Materials and methods
Discussion We have provided evidence of a cooperative interaction between FGFR4 and EGFR in the context of EGFR-dependent lung adenocarcinoma, which is independent of EGFR activating mutations. This cooperation is likely to occur through a physical interaction between both receptors leading to their overactivation and to EGFR therapy resistance, as shown by our in vitro, in vivo and clinical evidence. In addition, we have shown that a combination of EGFR and FGFR inhibitors may offer an effective therapeutic approach for tumors with both high EGFR activation and FGFR4 expression. Several examples in the literature describe cooperation between different RTKs in a variety of tumoral contexts, leading to therapy resistance similar to that described here. The IGF1R receptor, for instance, interacts with the insulin receptor in cell lines derived from gastric and liver tumors, correlating with higher AKT and STAT3 activation . EGFR itself has been shown to physically interact with PDGFRβ in SKL2001 what cancer, and with IGFR1 in lung cancer, leading to increased EGFR inhibitor resistance [29,30]. In fact, a potential relationship between EGFR and another member of the FGFR family, FGFR1, has been proposed in the head and neck carcinoma setting, which gives rise to FGFR inhibition resistance. In this work we have shown that FGFR4 interacts with EGFR and that when they are co-expressed, one is able to activate the other, leading to increased oncogenic signaling in vitro and in vivo. In line with our results, a previous report showed that FGFR4 expression is induced in MEFs transformed by EGFR overexpression, in contrast to MEFs transformed by other means . FGFR4 overexpression in this context, as shown by our results, may further activate EGFR, which could confer a selective growth and tumorigenic advantage, thus providing an explanation for this observed phenotype. Furthermore, our results show that the EGFR-FGFR4 cooperation confers EGFR inhibition resistance in vitro and in vivo. Consistent with this, we have shown that FGFR4 expression is predictive of EGFR inhibition efficacy in NSCLC patients. The role of other FGFR family members in EGFR inhibition resistance has been described in several published works, with FGFR1/FGFR2 upregulation as well as FGFR3 mutations known to be resistance mechanisms to anti-EGFR therapy [, , , , ], for which the combined use of EGFR and FGFR inhibitors has been proposed. Indeed, the inhibition of FGFR2 causes increased sensitivity to erlotinib in vitro in some lung cancer models . However, we are the first to describe such a role for FGFR4. In addition, the previous studies were focused mainly on the role of these FGFRs in acquired resistance after EGFR inhibitor treatment. Nonetheless, we show that FGFR4 overexpression can occur in tumors before their exposure to EGFR inhibitors, leading to intrinsic anti-EGFR therapy resistance, as our patient cohort had not received previous EGFR inhibition therapy. Taken together, these findings suggest a potential close interaction between EGFR and FGFRs, which may be interesting to explore in order to identify other FGFRs in different tumoral settings.