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Ref Type Journal Article
PMID (35948633)
Authors Zingg D, Bhin J, Yemelyanenko J, Kas SM, Rolfs F, Lutz C, Lee JK, Klarenbeek S, Silverman IM, Annunziato S, Chan CS, Piersma SR, Eijkman T, Badoux M, Gogola E, Siteur B, Sprengers J, de Klein B, de Goeij-de Haas RR, Riedlinger GM, Ke H, Madison R, Drenth AP, van der Burg E, Schut E, Henneman L, van Miltenburg MH, Proost N, Zhen H, Wientjens E, de Bruijn R, de Ruiter JR, Boon U, de Korte-Grimmerink R, van Gerwen B, Féliz L, Abou-Alfa GK, Ross JS, van de Ven M, Rottenberg S, Cuppen E, Chessex AV, Ali SM, Burn TC, Jimenez CR, Ganesan S, Wessels LFA, Jonkers J
Title Truncated FGFR2 is a clinically actionable oncogene in multiple cancers.
Journal Vol Issue Date Pages Journal Short Title
Nature 608 7923 2022 08 609-617 Nature
URL
Abstract Text Somatic hotspot mutations and structural amplifications and fusions that affect fibroblast growth factor receptor 2 (encoded by FGFR2) occur in multiple types of cancer1. However, clinical responses to FGFR inhibitors have remained variable1-9, emphasizing the need to better understand which FGFR2 alterations are oncogenic and therapeutically targetable. Here we apply transposon-based screening10,11 and tumour modelling in mice12,13, and find that the truncation of exon 18 (E18) of Fgfr2 is a potent driver mutation. Human oncogenomic datasets revealed a diverse set of FGFR2 alterations, including rearrangements, E1-E17 partial amplifications, and E18 nonsense and frameshift mutations, each causing the transcription of E18-truncated FGFR2 (FGFR2ΔE18). Functional in vitro and in vivo examination of a compendium of FGFR2ΔE18 and full-length variants pinpointed FGFR2-E18 truncation as single-driver alteration in cancer. By contrast, the oncogenic competence of FGFR2 full-length amplifications depended on a distinct landscape of cooperating driver genes. This suggests that genomic alterations that generate stable FGFR2ΔE18 variants are actionable therapeutic targets, which we confirmed in preclinical mouse and human tumour models, and in a clinical trial. We propose that cancers containing any FGFR2 variant with a truncated E18 should be considered for FGFR-targeted therapies.

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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
FGFR2 E768* nonsense gain of function - predicted FGFR2 E768* results in a premature truncation of the Fgfr2 protein at amino acid 768 of 821 (UniProt.org). E768* is predicted to lead to a gain of Fgfr2 protein function as a corresponding mouse variant (E673*) activates FGFR2 signaling and promotes colony formation in cell culture, and leads to tumor formation in a mouse model (PMID: 35948633).
FGFR2 L776Rfs*6 frameshift gain of function - predicted FGFR2 L776Rfs*6 indicates a shift in the reading frame starting at amino acid 776 and terminating six residues downstream causing a premature truncation of the 821 amino acid Fgfr2 protein (UniProt.org). L776Rfs*6 is predicted to lead to a gain of Fgfr2 protein function as a corresponding mouse variant (L681Rfs*6) promotes colony formation in cell culture and leads to tumor formation in a mouse model (PMID: 35948633).
FGFR2 P781* nonsense gain of function - predicted FGFR2 P781* results in a premature truncation of the Fgfr2 protein at amino acid 781 of 821 (UniProt.org). P781* is predicted to lead to a gain of Fgfr2 protein function as a corresponding mouse variant (P686*) promotes colony formation in cell culture and leads to tumor formation in a mouse model (PMID: 35948633).
FGFR2 S782Rfs*3 frameshift gain of function - predicted FGFR2 S782Rfs*3 indicates a shift in the reading frame starting at amino acid 776 and terminating 6 residues downstream causing a premature truncation of the 821 amino acid Fgfr2 protein (UniProt.org). S782Rfs*3 is predicted to lead to a gain of Fgfr2 protein function as a corresponding mouse variant (S687Rfs*3) promotes colony formation in cell culture and leads to tumor formation in a mouse model (PMID: 35948633).
FGFR2 S789* nonsense gain of function - predicted FGFR2 S789* results in a premature truncation of the Fgfr2 protein at amino acid 789 of 821 (UniProt.org). S789* is predicted to lead to a gain of Fgfr2 protein function as a corresponding mouse variant (S694*) promotes colony formation in cell culture and leads to tumor formation in a mouse model (PMID: 35948633).
FGFR2 S792Ffs*4 frameshift unknown FGFR2 S792Ffs*4 indicates a shift in the reading frame starting at amino acid 792 and terminating four residues downstream causing a premature truncation of the 821 amino acid Fgfr2 protein (UniProt.org). S792Ffs*4 (corresponding to S697Ffs*4 in a mouse isoform) leads to limited increase in FGFR2 signaling and colony formation in cell culture but promotes tumor formation in a mouse model (PMID: 35948633), and therefore, its effect on Fgfr2 protein function is unknown.
FGFR2 V797* nonsense unknown FGFR2 V797* results in a premature truncation of the Fgfr2 protein at amino acid 797 of 821 (UniProt.org). V797* (corresponding to V702* in a mouse isoform) leads to limited increase in FGFR2 signaling and colony formation in cell culture but promotes tumor formation in a mouse model (PMID: 35948633), and therefore, its effect on Fgfr2 protein function is unknown.
FGFR2 Y769* nonsense gain of function - predicted FGFR2 Y769* results in a premature truncation of the Fgfr2 protein at amino acid 769 of 821 (UniProt.org). Y769* is predicted to lead to a gain of Fgfr2 protein function as a corresponding mouse variant (Y674*) promotes colony formation in cell culture and leads to tumor formation in a mouse model (PMID: 35948633).
FGFR2 Y812* nonsense unknown FGFR2 Y812* results in a premature truncation of the Fgfr2 protein at amino acid 812 of 821 (UniProt.org). Y812* (corresponding to Y717* in a mouse isoform) leads to limited increase in FGFR2 signaling and colony formation in cell culture but promotes tumor formation in a mouse model (PMID: 35948633), and therefore, its effect on Fgfr2 protein function is unknown.
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR2 Y769* breast cancer predicted - sensitive Pemigatinib Preclinical - Cell culture Actionable In a preclinical study, Pemazyre (pemigatinib) inhibited growth of mouse mammary epithelial cells expressing FGFR2 Y674* (corresponding to Y769* in human) in culture (PMID: 35948633). 35948633
FGFR2 P781* breast cancer predicted - sensitive Pemigatinib Preclinical - Cell culture Actionable In a preclinical study, Pemazyre (pemigatinib) inhibited growth of mouse mammary epithelial cells expressing FGFR2 P686* (corresponding to P781* in human) in culture (PMID: 35948633). 35948633
FGFR2 C382R breast cancer predicted - sensitive Fexagratinib Preclinical - Cell culture Actionable In a preclinical study, AZD4547 inhibited growth of mouse mammary epithelial cells expressing FGFR2 C287R (corresponding to C382R in human) in culture (PMID: 35948633). 35948633
FGFR2 P781* breast cancer predicted - sensitive Fexagratinib Preclinical - Cell culture Actionable In a preclinical study, AZD4547 inhibited growth of mouse mammary epithelial cells expressing FGFR2 P686* (corresponding to P781* in human) in culture (PMID: 35948633). 35948633
FGFR2 E768* breast cancer predicted - sensitive Fexagratinib Preclinical Actionable In a preclinical study, AZD4547 inhibited FGFR2 signaling and growth in mouse mammary epithelial cells expressing FGFR2 E673* (corresponding to E768* in human) in culture and inhibited tumor growth in an orthotopic model (PMID: 35948633). 35948633
FGFR2 E768* breast cancer predicted - sensitive Infigratinib Preclinical - Cell culture Actionable In a preclinical study, Truseltiq (infigratinib) inhibited growth of mouse mammary epithelial cells expressing FGFR2 E673* (corresponding to E768* in human) in culture (PMID: 35948633). 35948633
FGFR2 L776Rfs*6 breast cancer predicted - sensitive Pemigatinib Preclinical - Cell culture Actionable In a preclinical study, Pemazyre (pemigatinib) inhibited growth of mouse mammary epithelial cells expressing FGFR2 L681Rfs*6 (corresponding to L776Rfs*6 in human) in culture (PMID: 35948633). 35948633
FGFR2 E768* breast cancer predicted - sensitive Pemigatinib Preclinical - Cell culture Actionable In a preclinical study, Pemazyre (pemigatinib) inhibited growth of mouse mammary epithelial cells expressing FGFR2 E673* (corresponding to E768* in human) in culture (PMID: 35948633). 35948633
FGFR2 L776Rfs*6 breast cancer predicted - sensitive Fexagratinib Preclinical - Cell culture Actionable In a preclinical study, AZD4547 inhibited growth of mouse mammary epithelial cells expressing FGFR2 L681Rfs*6 (corresponding to L776Rfs*6 in human) in culture (PMID: 35948633). 35948633
FGFR2 E768* breast cancer predicted - sensitive Zoligratinib Preclinical - Cell culture Actionable In a preclinical study, Debio 1347 inhibited growth of mouse mammary epithelial cells expressing FGFR2 E673* (corresponding to E768* in human) in culture (PMID: 35948633). 35948633
FGFR2 Y769* breast cancer predicted - sensitive Fexagratinib Preclinical - Cell culture Actionable In a preclinical study, AZD4547 inhibited growth of mouse mammary epithelial cells expressing FGFR2 Y674* (corresponding to Y769* in human) in culture (PMID: 35948633). 35948633
FGFR2 C382R breast cancer predicted - sensitive Pemigatinib Preclinical - Cell culture Actionable In a preclinical study, Pemazyre (pemigatinib) inhibited growth of mouse mammary epithelial cells expressing FGFR2 C287R (corresponding to C382R in human) in culture (PMID: 35948633). 35948633