FGFR1 is a potential therapeutic target in neuroblastoma

Abstract

Background FGFR1 regulates cell–cell adhesion and extracellular matrix architecture and acts as oncogene in several cancers. Potential cancer driver mutations of FGFR1 occur in neuroblastoma (NB), a neural crest-derived pediatric tumor arising in sympathetic nervous system, but so far they have not been studied experimentally. We investigated the driver-oncogene role of FGFR1 and the implication of N546K mutation in therapy-resistance in NB cells. Methods Public datasets were used to predict the correlation of FGFR1 expression with NB clinical outcomes. Whole genome sequencing data of 19 paired diagnostic and relapse NB samples were used to find somatic mutations. In NB cell lines, silencing by short hairpin RNA and transient overexpression of FGFR1 were performed to evaluate the effect of the identified mutation by cell growth, invasion and cologenicity assays. HEK293, SHSY5Y and SKNBE2 were selected to investigate subcellular wild-type and mutated protein localization. FGFR1 inhibitor (AZD4547), alone or in combination with PI3K inhibitor (GDC0941), was used to rescue malignant phenotypes induced by overexpression of FGFR1 wild-type and mutated protein. Results High FGFR1 expression correlated with low relapse-free survival in two independent NB gene expression datasets. In addition, we found the somatic mutation N546K, the most recurrent point mutation of FGFR1 in all cancers and already reported in NB, in one out of 19 matched primary and recurrent tumors. Loss of FGFR1 function attenuated invasion and cologenicity in NB cells, whereas FGFR1 overexpression enhanced oncogenicity. The overexpression of FGFR1N546K protein showed a higher nuclear localization compared to wild-type protein and increased cellular invasion and cologenicity. Moreover, N546K mutation caused the failure in response to treatment with FGFR1 inhibitor by activation of ERK, STAT3 and AKT pathways. The combination of FGFR1 and PI3K pathway inhibitors was effective in reducing the invasive and colonigenic ability of cells overexpressing FGFR1 mutated protein. Conclusions FGFR1 is an actionable driver oncogene in NB and a promising therapy may consist in targeting FGFR1 mutations in patients with therapy-resistant NB.

Potential Cause-and-Effect Relationship between Gut Microbiota and Childhood Neuroblastoma: A Mendelian Randomization Analysis

“…Mucin-4 (MUC4) is a secreted glycoprotein [14] non-amplified MYCN [15]. In this study, MUC4 was significantly negatively correlated with FGFR1, which regulates cell-cell adhesion and extracellular matrix architecture and acts as an oncogene in NB [16]. These results suggest that MUC4 may act as a tumor suppressor in NB.…”

Pro-metastatic and mesenchymal gene expression signatures characterize circulating tumor cells of neuroblastoma patients with bone marrow metastases and relapse

“…Comparing the 8 genes against reference human genome using over-representation testing, they were enriched for REACTOME pathways related to signaling by FGFR1, FGFR3 and FGFR4 (log 2 fold change >6.6) and GPCR downstream signaling (log 2 fold change 4.4), and PANTHER pathways related to PI3K signaling (log 2 fold change 6.5) (FDR adjusted P-value <0.05, Fisher exact test). Given their known function in tumor metastases ( 37 , 38 ), the overexpression of these genes in the CTCs of neuroblastoma patients with bone marrow metastases indicated potential pro-metastatic processes in the CTCs of neuroblastoma patients that could play a role in development of bone marrow metastases.…”

Genomic Analysis Made It Possible to Identify Gene-Driver Alterations Covering the Time Window between Diagnosis of Neuroblastoma 4S and the Progression to Stage 4

“…FGFR1 is a tyrosine kinase receptor whose inhibitors have been used extensively in Phase I/II clinical trials for treatment in cancers presenting FGFR1 mutation [ 49 ]. It was noted that the combination of AZD4547 and GDC0941 inhibits the activating effects of the FGFR1 mutation in NB cells in vitro [ 50 ].…”