Abstract
Deregulation of fibroblast growth factor receptors (FGFRs) signaling, as a result of FGFR amplification, chromosomal translocation, or mutations, is involved in both initiation and progression of a wide range of human cancers. Clinical data demonstrating the dependence of cancer cells on FGFRs signaling clearly indicate these receptors as the molecular targets of anti-cancer therapies. Despite the increasing number of tyrosine kinase inhibitors (TKIs) being investigated in clinical trials, acquired resistance to these drugs poses a serious therapeutic problem. In this study, we focused on a novel pan-FGFR inhibitor—CPL304110, currently being investigated in phase I clinical trials in adults with advanced solid malignancies. We analyzed the sensitivity of 17 cell lines derived from cancers with aberrant FGFR signaling, i.e. non-small cell lung cancer, gastric and bladder cancer to CPL304110. In order to explore the mechanism of acquired resistance to this FGFR inhibitor, we developed from sensitive cell lines their variants resistant to CPL304110. Herein, for the first time we revealed that the process of acquired resistance to the novel FGFR inhibitor was associated with increased expression of MET in lung, gastric, and bladder cancer cells. Overexpression of MET in NCI-H1703, SNU-16, RT-112 cells as well as treatment with HGF resulted in the impaired response to inhibition of FGFR activity. Moreover, we demonstrated that cells with acquired resistance to FGFR inhibitor as well as cells overexpressing MET displayed enhanced migratory abilities what was accompanied with increased levels of Pyk2 expression. Importantly, inhibition of both MET and Pyk2 activity restored sensitivity to FGFR inhibition in these cells. Our results demonstrate that the HGF/MET-Pyk2 signaling axis confers resistance to the novel FGFR inhibitor, and this mechanism is common for lung, gastric, and bladder cancer cells. Our study suggests that targeting of MET/Pyk2 could be an approach to overcome resistance to FGFR inhibition.
Highlights
The fibroblast growth factor receptor family comprises four (FGFR1-4) receptor tyrosine kinases (RTKs) involved in the regulation of many downstream effectors including mitogenactivated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K)/Akt, or STATs, that are crucial for cell proliferation, survival, differentiation, and motility (1, 2)
As amplification/overexpression of FGFR1, FGFR2, and FGFR3 contributes to progression of lung, gastric, and bladder cancers, respectively, we verified their level of expression in all analyzed cell lines (4, 24, 31–35)
As FGFR1 is overexpressed in approx. 20% of non-small cell lung cancer (4), the NCI-H1703 non-small cell lung cancer cell line was used for further studies
Summary
The fibroblast growth factor receptor family comprises four (FGFR1-4) receptor tyrosine kinases (RTKs) involved in the regulation of many downstream effectors including mitogenactivated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K)/Akt, or STATs, that are crucial for cell proliferation, survival, differentiation, and motility (1, 2). FGFR1 amplification has been identified in 10–20% of patients with non-small cell lung cancer whereas 4–10% of primary gastric cancers and approximately 75% of bladder cancers harbor FGFR2 amplification and FGFR3 mutations, respectively (7–10) These clinical data demonstrate the dependence of cancer cells on FGFR signaling and suggest an urgent requirement of molecular therapies targeting FGFR activity. Protein kinase C (PKC)-mediated phosphorylation of GSK-3b which led to activation of downstream pro-survival proteins was identified as a mechanism of resistance to AZD4547 in gastric cancer cell lines (18). These data indicate the complexity of acquired resistance to FGFR inhibition and pose a significant challenge to identify common pathways responsible for resistance in various cancers
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