Reference Detail

Ref Type

Journal Article

PMID

(33926920)

Authors

Cleary JM, Raghavan S, Wu Q, Li YY, Spurr LF, Gupta HV, Rubinson DA, Fetter IJ, Hornick JL, Nowak JA, Siravegna G, Goyal L, Shi L, Brais LK, Loftus M, Shinagare AB, Abrams TA, Clancy TE, Wang J, Patel AK, Brichory F, Vaslin Chessex A, Sullivan RJ, Keller RB, Denning S, Hill ER, Shapiro GI, Pokorska-Bocci A, Zanna C, Ng K, Schrag D, Jänne PA, Hahn WC, Cherniack AD, Corcoran RB, Meyerson M, Daina A, Zoete V, Bardeesy N, Wolpin BM

Title

FGFR2 Extracellular Domain In-Frame Deletions Are Therapeutically Targetable Genomic Alterations That Function as Oncogenic Drivers in Cholangiocarcinoma.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer discovery	11	10	2021 Oct	2488-2505	Cancer Discov

URL

Abstract Text

We conducted next-generation DNA sequencing on 335 biliary tract cancers and characterized the genomic landscape by anatomic site within the biliary tree. In addition to frequent FGFR2 fusions among patients with intrahepatic cholangiocarcinoma (IHCC), we identified FGFR2 extracellular domain in-frame deletions (EID) in 5 of 178 (2.8%) patients with IHCC, including two patients with FGFR2 p.H167_N173del. Expression of this FGFR2 EID in NIH3T3 cells resulted in constitutive FGFR2 activation, oncogenic transformation, and sensitivity to FGFR inhibitors. Three patients with FGFR2 EIDs were treated with Debio 1347, an oral FGFR1/2/3 inhibitor, and all showed partial responses. One patient developed an acquired L618F FGFR2 kinase domain mutation at disease progression and experienced a further partial response for 17 months to an irreversible FGFR2 inhibitor, futibatinib. Together, these findings reveal FGFR2 EIDs as an alternative mechanism of FGFR2 activation in IHCC that predicts sensitivity to FGFR inhibitors in the clinic. SIGNIFICANCE: FGFR2 EIDs are transforming genomic alterations that occur predominantly in patients with IHCC. These FGFR2 EIDs are sensitive to FGFR inhibition in vitro , and patients with these alterations benefited from treatment with FGFR inhibitors in the clinic. This article is highlighted in the In This Issue feature, p. 2355 .

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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	exon 5 del	deletion	unknown	FGFR2 exon 5 deletions are in-frame deletions within the extracellular domain of the Fgfr2 protein (PMID: 33926920).
FGFR2	exon 7 del	deletion	unknown	FGFR2 exon 7 deletions are in-frame deletions within the extracellular domain of the Fgfr2 protein (PMID: 33926920).
FGFR2	H167_N173del	deletion	gain of function	FGFR2 H167_N173del results in the deletion of seven amino acids in Ig-like C2-type domain 2 of the Fgfr2 protein from amino acids 167 to 173 (UniProt.org). H167_N173del results in cell transformation (J Clin Oncol 38, 2020 (suppl 4; abstr 567), PMID: 33926920), increased proliferation, invasion, and migration (PMID: 37964396), anchorage-independent growth, constitutive activation of Fgfr2 kinase activity in culture, and tumor formation in an in vivo model (PMID: 33926920).
FGFR2	I288_E295delinsT	indel	unknown	FGFR2 I288_E295delinsT results in deletion of eight amino acids in Ig-like C2-type domain 3 of the Fgfr2 protein from amino acids 288 to 295, combined with the insertion of a threonine (T) at the same location (UniProt.org). I288_E295delinsT has been identified in the scientific literature (PMID: 33926920), but has not been biochemically characterized and therefore, its effect on Fgfr2 protein function is unknown (PubMed, Nov 2024).
FGFR2	L618F	missense	unknown	FGFR2 L618F (corresponds to L617F in the canonical isoform) lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). L618F in combination with FGFR2 H167_N173del results in constitutive FGFR2 signaling in culture (PMID: 33926920), and has been shown to be associated with secondary resistance to FGFR inhibitors (PMID: 33926920, PMID: 37843855), but has not been individually characterized and therefore, its effect on Fgfr2 protein function is unknown (PubMed, Nov 2024).	Y

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FGFR2 H167_N173del	intrahepatic cholangiocarcinoma	predicted - sensitive	Zoligratinib	Case Reports/Case Series	Actionable	In a Phase I trial, Debio 1347 treatment led to 51% tumor reduction and a progression-free survival of 13 months in an intrahepatic cholangiocarcinoma patient harboring FGFR2 H167_N173del, which was consistent with inhibition of growth in an intrahepatic cholangiocarcinoma cell line expressing FGFR2 H167_N173del in culture (PMID: 33926920; NCT01948297).	33926920
FGFR2 I288_E295delinsT	intrahepatic cholangiocarcinoma	predicted - sensitive	Zoligratinib	Case Reports/Case Series	Actionable	In a clinical case study, Debio 1347 treatment in an intrahepatic cholangiocarcinoma patient harboring FGFR2 I288_E295delinsT led to a partial response with a 50% decrease in tumor burden, which was ongoing after 24 months (PMID: 33926920).	33926920
BRAF L597Q FGFR2 H167_N173del FGFR2 N550K FGFR2 L618F NRAS Q61K	intrahepatic cholangiocarcinoma	predicted - resistant	LY3214996	Case Reports/Case Series	Actionable	In a clinical case study, acquired NRAS Q61K and FGFR2 N550K mutations were identified following progression on LY3214996 in an intrahepatic cholangiocarcinoma patient harboring BRAF L597Q, FGFR2 H167_N173del, and FGFR2 L618F (PMID: 33926920).	33926920
BRAF L597Q FGFR2 H167_N173del FGFR2 L618F	intrahepatic cholangiocarcinoma	predicted - resistant	Futibatinib	Case Reports/Case Series	Actionable	In a clinical case study, acquisition of BRAF L597Q was identified in an intrahepatic cholangiocarcinoma patient harboring FGFR2 H167_N173del and FGFR2 L618F who developed resistance to treatment with Lytgobi (futibatinib) (PMID: 33926920).	33926920
FGFR2 H167_N173del	marginal zone lymphoma	predicted - sensitive	Zoligratinib	Preclinical - Cell culture	Actionable	In a clinical case study, Debio 1347 treatment in a marginal zone lymphoma patient harboring FGFR2 H167_N173del, who had previously been treated with several lines of therapy, led to a partial response and 36% decrease in tumor burden associated with lymphadenopathy and lung and liver lesions at 16 weeks, with continued response after 7 months (PMID: 33926920).	33926920
FGFR2 H167_N173del FGFR2 L618F	intrahepatic cholangiocarcinoma	predicted - resistant	Zoligratinib	Case Reports/Case Series	Actionable	In a Phase I trial, an intrahepatic cholangioncarcinoma patient who progressed in Debio 1347 was found to have acquired FGFR2 L618F, and co-expression of FGFR2 H167_N173del and FGFR2 L618F an intrahepatic cholangiocarcinoma cell line led to a reduced response to Debio 1347 treatment compared to cells expressing wild-type FGFR2 in culture (PMID: 33926920).	33926920
FGFR2 H167_N173del FGFR2 L618F	intrahepatic cholangiocarcinoma	predicted - sensitive	Futibatinib	Case Reports/Case Series	Actionable	In a Phase I trial, Lytgobi (futibatinib) treatment led to a partial response with 61% tumor reduction and response duration of 17 months in an intrahepatic cholangiocarcinoma patient harboring FGFR2 H167_N173del and FGFR2 L618F, which was consistent with inhibition of growth in an intrahepatic cholangiocarcinoma cell line expressing FGFR2 H167_N173del and FGFR2 L618F in culture (PMID: 33926920).	33926920
BRAF L597Q FGFR2 H167_N173del FGFR2 L618F	intrahepatic cholangiocarcinoma	no benefit	LY3214996	Case Reports/Case Series	Actionable	In a clinical case study, LY3214996 treatment led to progressive disease after 2 months in an intrahepatic cholangiocarcinoma patient harboring BRAF L597Q, FGFR2 H167_N173del, and FGFR2 L618F (PMID: 33926920).	33926920
FGFR2 H167_N173del	intrahepatic cholangiocarcinoma	predicted - sensitive	Futibatinib	Preclinical - Cell culture	Actionable	In a preclinical study, Lytgobi (futibatinib) inhibited growth of an intrahepatic cholangiocarcinoma cell line expressing FGFR2 H167_N173del in culture (PMID: 33926920).	33926920