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Ref Type Journal Article
PMID (23786770)
Authors Liao RG, Jung J, Tchaicha J, Wilkerson MD, Sivachenko A, Beauchamp EM, Liu Q, Pugh TJ, Pedamallu CS, Hayes DN, Gray NS, Getz G, Wong KK, Haddad RI, Meyerson M, Hammerman PS
Title Inhibitor-sensitive FGFR2 and FGFR3 mutations in lung squamous cell carcinoma.
Journal Vol Issue Date Pages Journal Short Title
Cancer research 73 16 2013 Aug 15 5195-205 Cancer Res
URL
Abstract Text A comprehensive description of genomic alterations in lung squamous cell carcinoma (lung SCC) has recently been reported, enabling the identification of genomic events that contribute to the oncogenesis of this disease. In lung SCC, one of the most frequently altered receptor tyrosine kinase families is the fibroblast growth factor receptor (FGFR) family, with amplification or mutation observed in all four family members. Here, we describe the oncogenic nature of mutations observed in FGFR2 and FGFR3, each of which are observed in 3% of samples, for a mutation rate of 6% across both genes. Using cell culture and xenograft models, we show that several of these mutations drive cellular transformation. Transformation can be reversed by small-molecule FGFR inhibitors currently being developed for clinical use. We also show that mutations in the extracellular domains of FGFR2 lead to constitutive FGFR dimerization. In addition, we report a patient with an FGFR2-mutated oral SCC who responded to the multitargeted tyrosine kinase inhibitor pazopanib. These findings provide new insights into driving oncogenic events in a subset of lung squamous cancers, and recommend future clinical studies with FGFR inhibitors in patients with lung and head and neck SCC.

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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
Pazopanib Pazopanib 14 49
Drug Name Trade Name Synonyms Drug Classes Drug Description
Pazopanib Votrient GW-786034 FGFR1 Inhibitor 28 FGFR2 Inhibitor 24 FGFR3 Inhibitor 20 KIT Inhibitor 57 PDGFR Inhibitor (Pan) 30 VEGFR Inhibitor (Pan) 36 Votrient (pazopanib) inhibits VEGFR-1, -2 and -3, KIT, and PDGFR, and FGFR1, 2, and 3, leading to decreased tumor angiogenesis and growth (PMID: 17620431, PMID: 23786770). Votrient (pazopanib) is approved for renal cell carcinoma and soft tissue sarcoma (FDA.gov).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
FGFR2 K659E missense gain of function FGFR2 K659E (also referred to as K660E from the FGFR2IIIb isoform) lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). K659E results in a growth advantage relative to wild-type Fgfr2 in a competition assay and increased transformation activity in cultured cells (PMID: 34272467), increased phosphorylation of downstream signaling molecules, induces colony formation in culture (PMID: 23786770), and results in the ability to induce senescence and cooperate with Myc to induce transformation of cell lines in culture (PMID: 19403560).
FGFR2 K660E missense gain of function FGFR2 K660E (corresponds to K659E in the canonical isoform) lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). K660E results in increased phosphorylation of Fgfr2, activation of downstream signaling, and is transforming in cell culture (PMID: 23786770). Y
FGFR2 P253R missense gain of function - predicted FGFR2 P253R lies within the extracellular domain of the Fgfr2 protein (UniProt.org). P253R results in transformation activity similar to wild-type Fgfr2 in one study (PMID: 34272467), but a growth advantage relative to wild-type Fgfr2 in a competition assay (PMID: 34272467), loss of ligand specificity, activation of the p38/MAPK pathway in transgenic mouse models, and is transforming in cell culture (PMID: 11121055, PMID: 20175913, PMID: 23786770), and therefore, is predicted to lead to a gain of Fgfr2 protein function.
FGFR2 W290C missense gain of function FGFR2 W290C lies within the Ig-like C2-type domain 3 of the Fgfr2 protein (UniProt.org). W290C does not result in increased Fgfr2 phosphorylation, but increases both ligand-dependent and ligand-independent dimerization of Fgfr2 (PMID: 23786770), results in a growth advantage relative to wild-type Fgfr2 in a competition assay (PMID: 34272467), is transforming in cell culture (PMID: 23786770, PMID: 34272467), and promotes tumor formation in xenograft models (PMID: 23786770).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR3 S249C Advanced Solid Tumor sensitive Infigratinib Preclinical - Cell culture Actionable In a preclinical study, Truseltiq (infigratinib) inhibited growth of transformed cells expressing FGFR3 S249C in culture (PMID: 23786770). 23786770
FGFR3 R248C Advanced Solid Tumor sensitive Pazopanib Preclinical - Cell culture Actionable In a preclinical study, Votrient (pazopanib) inhibited growth of transformed cells expressing FGFR3 R248C in culture (PMID: 23786770). 23786770
FGFR2 K660N Advanced Solid Tumor sensitive Cediranib Preclinical - Cell culture Actionable In a preclinical study, Cediranib (AZD-2171) inhibited growth of transformed cells expressing FGFR2 K660N in culture (PMID: 23786770). 23786770
FGFR2 K660N Advanced Solid Tumor sensitive Ponatinib Preclinical - Cell culture Actionable In a preclinical study, Iclusig (ponatinib) inhibited growth of transformed cells expressing FGFR2 K660N in culture (PMID: 23786770). 23786770
FGFR3 R248C Advanced Solid Tumor conflicting Dovitinib Preclinical - Cell culture Actionable In a preclinical study, Dovitinib (TKI258) inhibited growth of transformed cells expressing FGFR3 R248C in culture (PMID: 23786770). 23786770
FGFR2 P253R head and neck squamous cell carcinoma predicted - sensitive Pazopanib Case Reports/Case Series Actionable In a clinical case study, treatment with Votrient (pazopanib) resulted in reduced tumor size in a patient with head and neck squamous cell carcinoma harboring FGFR2 P253R (PMID: 23786770). 23786770
FGFR2 W290C Advanced Solid Tumor sensitive Fexagratinib Preclinical - Cell culture Actionable In a preclinical study, AZD4547 inhibited growth of transformed cells expressing FGFR2 W290C in culture (PMID: 23786770). 23786770
FGFR2 K660E Advanced Solid Tumor sensitive Cediranib Preclinical - Cell culture Actionable In a preclinical study, Cediranib (AZD-2171) inhibited growth of transformed cells expressing FGFR2 K660E in culture (PMID: 23786770). 23786770
FGFR2 K660E Advanced Solid Tumor sensitive Lenvatinib Preclinical - Cell culture Actionable In a preclinical study, Lenvima (lenvatinib) inhibited growth of transformed cells expressing FGFR2 K660E in culture (PMID: 23786770). 23786770
FGFR3 R248C Advanced Solid Tumor sensitive Infigratinib Preclinical - Cell culture Actionable In a preclinical study, Truseltiq (infigratinib) inhibited growth of transformed cells expressing FGFR3 R248C in culture (PMID: 23786770). 23786770
FGFR2 W290C Advanced Solid Tumor sensitive Lenvatinib Preclinical - Cell culture Actionable In a preclinical study, Lenvima (lenvatinib) inhibited growth of transformed cells expressing FGFR2 W290C in culture (PMID: 23786770). 23786770
FGFR2 W290C Advanced Solid Tumor sensitive Infigratinib Preclinical - Cell line xenograft Actionable In a preclinical study, Truseltiq (infigratinib) inhibited growth of transformed cells expressing FGFR2 W290C in culture and inhibited tumor growth in xenograft models (PMID: 23786770). 23786770
FGFR2 K660N Advanced Solid Tumor sensitive Lenvatinib Preclinical - Cell culture Actionable In a preclinical study, Lenvima (lenvatinib) inhibited growth of transformed cells expressing FGFR2 K660N in culture (PMID: 23786770). 23786770
FGFR2 K660E Advanced Solid Tumor sensitive Infigratinib Preclinical - Cell culture Actionable In a preclinical study, Truseltiq (infigratinib) inhibited growth of transformed cells expressing FGFR2 K660E in culture (PMID: 23786770). 23786770
FGFR2 W290C Advanced Solid Tumor sensitive Ponatinib Preclinical - Cell culture Actionable In a preclinical study, Iclusig (ponatinib) inhibited growth of transformed cells expressing FGFR2 W290C in culture (PMID: 23786770). 23786770
FGFR2 K660N Advanced Solid Tumor sensitive Infigratinib Preclinical - Cell line xenograft Actionable In a preclinical study, Truseltiq (infigratinib) inhibited growth of transformed cells expressing FGFR2 K660N in culture and inhibited tumor growth in xenograft models (PMID: 23786770). 23786770
FGFR3 S249C Advanced Solid Tumor conflicting Dovitinib Preclinical - Cell culture Actionable In a preclinical study, Dovitinib (TKI258) inhibited growth of transformed cells expressing FGFR3 S249C in culture (PMID: 23786770). 23786770
FGFR2 W290C Advanced Solid Tumor sensitive Pazopanib Preclinical - Cell culture Actionable In a preclinical study, Votrient (pazopanib) inhibited growth of transformed cells expressing FGFR2 W290C in culture (PMID: 23786770). 23786770
FGFR2 K660N Advanced Solid Tumor sensitive Fexagratinib Preclinical - Cell culture Actionable In a preclinical study, AZD4547 inhibited growth of transformed cells expressing FGFR2 K660N in culture (PMID: 23786770). 23786770
FGFR2 K660E Advanced Solid Tumor sensitive Fexagratinib Preclinical - Cell culture Actionable In a preclinical study, AZD4547 inhibited growth of transformed cells expressing FGFR2 K660E in culture (PMID: 23786770). 23786770
FGFR2 K660E Advanced Solid Tumor sensitive Pazopanib Preclinical - Cell culture Actionable In a preclinical study, Votrient (pazopanib) inhibited growth of transformed cells expressing FGFR2 K660E in culture (PMID: 23786770). 23786770
FGFR3 S249C Advanced Solid Tumor sensitive Ponatinib Preclinical - Cell culture Actionable In a preclinical study, Iclusig (ponatinib) inhibited growth of transformed cells expressing FGFR3 S249C in culture (PMID: 23786770). 23786770
FGFR2 K660N Advanced Solid Tumor sensitive Pazopanib Preclinical - Cell culture Actionable In a preclinical study, Votrient (pazopanib) inhibited growth of transformed cells expressing FGFR2 K660N in culture (PMID: 23786770). 23786770
FGFR2 W290C Advanced Solid Tumor sensitive Cediranib Preclinical - Cell culture Actionable In a preclinical study, Cediranib (AZD-2171) inhibited growth of transformed cells expressing FGFR2 W290C in culture (PMID: 23786770). 23786770