FGFR Inhibition Enhances Sensitivity to Radiation in Non–Small Cell Lung Cancer

Abstract

FGFRs are commonly altered in non-small cell lung cancer (NSCLC). FGFRs activate multiple pathways including RAS/RAF/MAPK, PI3K/AKT, and STAT, which may play a role in the cellular response to radiation. We investigated the effects of combining the selective FGFR 1-3 tyrosine kinase inhibitor AZD4547 with radiation in cell line and xenograft models of NSCLC. NSCLC cell lines were assessed with proliferation, clonogenic survival, apoptosis, autophagy, cell cycle, and DNA damage signaling and repair assays. In vivo xenografts and IHC were used to confirm in vitro results. NSCLC cell lines demonstrated varying degrees of FGFR protein and mRNA expression. In vitro clonogenic survival assays showed radiosensitization with AZD4547 in two NSCLC cell lines. In these two cell lines, an increase in apoptosis and autophagy was observed with combined radiation and AZD4547. The addition of AZD4547 to radiation did not significantly affect gH2AX foci formation. Enhanced xenograft tumor growth delay was observed with the combination of radiation and AZD4547 compared with radiation or drug alone. IHC results revealed inhibition of pMAPK and pS6 and demonstrated an increase in apoptosis in the radiation plus AZD4547 group. This study demonstrates that FGFR inhibition by AZD4547 enhances the response of radiation in FGFR-expressing NSCLC in vitro and in vivo model systems. These results support further investigation of combining FGFR inhibition with radiation as a clinical therapeutic strategy.

Burn Ointment Promotes Cutaneous Wound Healing by Modulating the PI3K/AKT/mTOR Signaling Pathway

“…The immunohistochemistry (IHC) Image Analysis Toolbox Plug-tool was first used to identify areas of positive staining. Thirty-six images were then converted to the RGB scale and the threshold tool was used to calculate the percentage area positively stained ( SenthilKumar et al, 2020 ).…”

Clinical Impact of the Epithelial-Mesenchymal Transition in Lung Cancer as a Biomarker Assisting in Therapeutic Decisions

“…2) also constitutes a clear challenge in targeting EMTs [Zoni et al, 2015;Yin et al, 2019] and pleads in favor of multitarget TKI approaches that are being examined [de Jonge et al, 2019;Hellerstedt et al, 2019;Wheatley-Price et al, 2019]. Multiple therapeutics against EMT-activating pathways (e.g., TGFβ, FAK, FGFR, or PDGFR) have been tested with no convincing effects [Giaccone et al, 2015;Paik et al, 2017;Han et al, 2018;Gerber et al, 2020], although research is still ongoing with FGFR [SenthilKumar et al, 2020] or FAK inhibitors [Mak et al, 2019]. Among EMT-associated targetable receptor pathways, AXL seems currently EMT in Lung Cancer Management 13 Cells Tissues Organs DOI: 10.1159/000510103 one of the most promising [C. .…”

Genomic Profiling Reveals Novel Predictive Biomarkers for Chemo-Radiotherapy Efficacy and Thoracic Toxicity in Non-Small-Cell Lung Cancer

“…No difference in survival was observed between FGFR1 wildtype and mutant patients (HR [95% CI] = 1.41 [0.56-3.56], P =0.46, Figure 3B ). Given that FGFR signaling is often dysregulated in NSCLC and have been implicated in radiation resistance in preclinical studies ( 23 , 24 ), we sought to further test the association between FGFR family genes and patient survival. Indeed, we found that genetic alterations in the FGFR family receptors, including FGFR1 - 4 , were associated with earlier progression (PFS, HR [95% CI] = 1.72 [1.06-2.79], P =0.03; OS, HR [95% CI] = 2.04 [1.14-3.65], P =0.01, Figures 3C, D ).…”

“…Emerging evidence suggest that FGFR may be implicated in variable response to radiotherapy. Pre-clinical studies in NSCLC cell lines, xenograft models and genetically engineered mouse models have shown that FGFR inhibition can enhance radiation response, which may be through the upregulation of cellular apoptosis and autophagy ( 23 ) and/or polarization of tumor-associated macrophages towards the M1 phenotype ( 24 ). In our study, we provide the first clinical evidence for the role of FGFR in mediating dCRT response.…”