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Ref Type Journal Article
PMID (37778450)
Authors Domenichini M, Ravelli C, Corsini M, Codenotti S, Moreschi E, Gogna A, Capoferri D, Zizioli D, Bresciani R, Grillo E, Mitola S
Title The D647N mutation of FGFR1 induces ligand-independent receptor activation.
Journal Vol Issue Date Pages Journal Short Title
Biochimica et biophysica acta. General subjects 1867 12 2023 Dec 130470 Biochim Biophys Acta Gen Subj
URL
Abstract Text The activation loop (A-loop) of kinases, a key regulatory region, is recurrently mutated in several kinase proteins in cancer resulting in dysregulated kinase activity and response to kinase inhibitors. FGFR1 receptor tyrosine kinase represents an important oncogene and therapeutic target for solid and hematological tumors. Here we investigate the biochemical and molecular effects of D647N mutation lying in the A-loop of FGFR1. When expressed in normal and tumoral in vitro cell models, FGFR1D647N is phosphorylated also in the absence of ligands, and this is accompanied by the activation of intracellular signaling. The expression of FGFR1D647N significantly increases single and collective migration of cancer cells in vitro and in vivo, when compared to FGFR1WT. FGFR1D647N expression exacerbates the aggressiveness of cancer cells, increasing their invasiveness in vitro and augmenting their pro-angiogenic capacity in vivo. Remarkably, the D647N mutation significantly increases the sensitivity of FGFR1 to the ATP-competitive inhibitor Erdafitinib suggesting the possibility that this mutation could become a specific target for the development of new inhibitors. Although further efforts are warranted for an exhaustive description of the activation mechanisms, for the identification of more specific inhibitors and for confirming the clinical significance of mutated FGFR1D647N, overall our data demonstrate that the D647N substitution of FGFR1 is a novel pro-oncogenic activating mutation of the receptor that, when found in cancer patients, may anticipate good response to erdafitinib treatment.

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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 D647N missense gain of function FGFR1 D647N lies within the protein kinase domain of the Fgfr1 protein (UniProt.org). D647N demonstrates ATP affinity similar to wild-type Fgfr1 (PMID: 37778450), but results in increased ligand-independent phosphorylation of Fgfr1 (PMID: 34826586, PMID: 37778450), downstream signaling, migration, invasion, and angiogenesis in culture (PMID: 37778450).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR1 D647N breast cancer sensitive Erdafitinib Preclinical - Cell culture Actionable In a preclinical study, Balversa (erdafitinib) treatment resulted in decreased Fgfr1 phosphorylation in a cell line expressing FGFR1 D647N and reduced migration in breast cancer cells expressing FGFR1 D647N in culture (PMID: 37778450). 37778450