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|Ref Type||Journal Article|
|Authors||Cimmino F, Montella A, Tirelli M, Avitabile M, Lasorsa VA, Visconte F, Cantalupo S, Maiorino T, De Angelis B, Morini M, Castellano A, Locatelli F, Capasso M, Iolascon A|
|Title||FGFR1 is a potential therapeutic target in neuroblastoma.|
|Journal||Cancer cell international|
|Date||2022 Apr 29|
|Abstract Text||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.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.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.FGFR1 is an actionable driver oncogene in NB and a promising therapy may consist in targeting FGFR1 mutations in patients with therapy-resistant NB.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|FGFR1||N546K||missense||gain of function||FGFR1 N546K lies within the protein kinase domain of the Fgfr1 protein (UniProt.org). N546K does not confer a growth advantage in a competition assay (PMID: 34272467), but results in increased Fgfr1 protein nuclear localization, Erk, Akt, and Stat3 phosphorylation (PMID: 35488346), and kinase activity, and is transforming in cultured cells (PMID: 26179511, PMID: 23817572, PMID: 29533785).|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|FGFR1 N546K||neuroblastoma||sensitive||AZD4547 + Pictilisib||Preclinical - Cell culture||Actionable||In a preclinical study, the combination of AZD4547 and Pictilisib (GDC-0941) resulted in greater inhibition of FGFR1 signaling, cell invasion, and colony formation compared to AZD4547 alone in neuroblastoma cell lines expressing FGFR1 N546K in culture (PMID: 35488346).||35488346|