FGFR1 mRNA and Protein Expression, not Gene Copy Number, Predict FGFR TKI Sensitivity across All Lung Cancer Histologies

Mw, Wynes; Tk, Hinz; D, Gao; Martini, Miriam; La, Marek; Ke, Ware; Mg, Edwards; Böhm, Diana; Perner, Sven; Ba, Helfrich; Dziadziuszko, Rafał; Jassem, Jacek; Wojtylak, Szymon; Sejda, Aleksandra; Jm, Gozgit; Pa, Bunn; Dr, Camidge; Tan, Aik Choon; Fr, Hirsch; Le, Heasley

doi:10.1158/1078-0432.ccr-13-3060

Cited by 145 publications

(180 citation statements)

References 25 publications

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“…This phenomenon was evident for all analyzed Ewing sarcoma cell lines and was observed in vitro as well as in vivo. The efficacy of shRNA-based FGFR1 knockdown was far more prominent in Ewing sarcoma than in several other cancer types, such as lung cancer, which had previously been described to be associated with FGFR1 activity (42). Ponatinib as a FGFR1 inhibitor (39) showed significant activity toward proliferation of Ewing sarcoma cell lines in our experiments.…”

Section: Discussionsupporting

confidence: 51%

“…Accordingly, FGFR1 was highly expressed on the protein level in almost all analyzed Ewing sarcoma. Gene amplification and overexpression are crucial pathogenetic mechanisms for growth factor receptors activation in multiple cancers (42,43). For example, EGFR amplification and overexpression with subsequent auto-activation has been described in breast cancer and lung cancer.…”

Section: Discussionmentioning

confidence: 99%

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Deep Sequencing in Conjunction with Expression and Functional Analyses Reveals Activation of FGFR1 in Ewing Sarcoma

Agelopoulos

Richter

Schmidt

et al. 2015

Clinical Cancer Research

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PURPOSE: A low mutation rate seems to be a general feature of pediatric cancers, in particular in oncofusion gene-driven tumors. Genetically, Ewing sarcoma is defined by balanced chromosomal EWS/ETS translocations, which give rise to oncogenic chimeric proteins (EWS-ETS). Other contributing somatic mutations involved in disease development have only been observed at low frequency. EXPER-IMENTAL DESIGN: Tumor samples of 116 Ewing sarcoma patients were analyzed here. Whole-genome sequencing was performed on two patients with normal, primary, and relapsed tissue. Whole-exome sequencing was performed on 50 Ewing sarcoma and 22 matched normal tissues. A discovery dataset of 14 of these tumor/normal pairs identified 232 somatic mutations. Recurrent nonsynonymous mutations were validated in the 36 remaining exomes. Transcriptome analysis was performed in a subset of 14 of 50 Ewing sarcomas and DNA copy number gain and expression of FGFR1 in 63 of 116 Ewing sarcomas. RESULTS: Relapsed tumors consistently showed a 2-to 3-fold increased number of mutations. We identified several recurrently mutated genes at low frequency (ANKRD30A, CCDC19, KIAA0319, KIAA1522, LAMB4, SLFN11, STAG2, TP53, UNC80, ZNF98). An oncogenic fibroblast growth factor receptor 1 (FGFR1) mutation (N546K) was detected, and the FGFR1 locus frequently showed copy number gain (31.7%) in primary tumors. Furthermore, high-level FGFR1 expression was noted as a characteristic feature of Ewing sarcoma. RNA interference of FGFR1 expression in Ewing sarcoma lines blocked proliferation and completely suppressed xenograft tumor growth. FGFR1 tyrosine kinase inhibitor (TKI) therapy in a patient with Ewing sarcoma relapse significantly reduced 18-FDG-PET activity. CONCLUSIONS: FGFR1 may constitute a promising target for novel therapeutic approaches in Ewing sarcoma.

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Section: Discussionsupporting

confidence: 51%

Section: Discussionmentioning

confidence: 99%

Deep Sequencing in Conjunction with Expression and Functional Analyses Reveals Activation of FGFR1 in Ewing Sarcoma

Agelopoulos

Richter

Schmidt

et al. 2015

Clinical Cancer Research

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“…We used validated models of FGFR1-amplified lung cancer: two squamous cell lines NCI-H520 and HCC95, and a small-cell lung cancer cell line DMS 114 (24), together with a non-amplified control squamous cell line HCC15 (29). Using Western blot analysis, we confirmed the presence of FGFR1 in all FGFR1-amplified lung cancer cell lines, whereas no detectable FGFR1 expression was observed in the HCC15 cell line (Fig.…”

Section: Internalization Of Scfvd2-fc Into Lung Cancer Cellsmentioning

confidence: 82%

“…According to recent studies, frequent amplification and overexpression of FGFR1 has been observed in tumor cells of a large proportion of squamous cell lung carcinoma patients (14,29) and a significant fraction of patients with small-cell lung cancer (17)(18)(19), while relatively little FGFR1 is found on non-tumor cells (42,43). Moreover, FGF receptors are localized to the plasma membrane which makes them accessible to various ligands coming from the bloodstream.…”

Section: Discussionmentioning

confidence: 99%

High-Affinity Internalizing Human scFv-Fc Antibody for Targeting FGFR1-Overexpressing Lung Cancer

Sokołowska-Wędzina

Chodaczek

Chudzian

et al. 2017

Molecular Cancer Research

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Targeted delivery of anticancer drugs using antibodies specific for tumor-associated antigens represents one of the most important approaches in current immuno-oncology research. Fibroblast growth factor receptor 1 (FGFR1) has been demonstrated to be a high-frequency targetable oncogene specific for smokingassociated lung cancers, present in over 20% of lung squamous cell carcinoma cases. This report describes the generation of a potent, fully human antibody fragment in scFv-Fc format efficiently targeting FGFR1. Antibody phage display was used to select high-affinity scFv antibody fragments against the extracellular domain of FGFR1(IIIc). Enzyme immunoassay (ELISA) and surface plasmon resonance (SPR) analysis were used for antibody screening and characterization. The best binder (named D2) was cloned to diabody and Fc fusion formats. All D2 antibodies demonstrated high affinity for FGFR1 with dissociation constants of 18 nmol/L (scFvD2), 0.82 nmol/L (scFvD2 diabody), and 0.59 nmol/L (scFvD2-Fc). scFvD2 was found to be exquisitely selective for FGFR1 versus other FGFR family members and bound FGFR1 even in the presence of its natural ligand FGF2, as shown by competitive analysis. Confocal microscopy revealed that scFvD2-Fc was specifically and rapidly internalized by a panel of cell lines overexpressing FGFR1. Finally, it was demonstrated that scFvD2-Fc mediated specific delivery of a cytotoxic payload into lung cancer cells harboring oncogenic FGFR1 gene amplifications.Implications: This study reports a highly specific internalizing antibody fragment that can serve as a therapeutic targeting agent for efficient delivery of cytotoxic drugs into FGFR1-positive lung cancer cells. Mol Cancer Res; 15(8); 1040-50. Ó2017 AACR.

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“…The validity of the RNAScope system for semiquantitative assessment of mRNA in formalin fixed paraffin-embedded tissues has been shown previously by other groups. [12][13][14] In the tested samples, nonneoplastic liver was consistently negative suggesting very low or absent expression of PRKACA in normal liver. In endothelial cells and lymphocytes, ISH staining was limited, with only 1 þ expression (1 dot per cell) in lymphocytes and endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

DNAJB1-PRKACA is specific for fibrolamellar carcinoma

et al. 2015

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Fibrolamellar carcinoma is a distinct subtype of hepatocellular carcinoma that predominantly affects young patients without underlying cirrhosis. A recurrent DNAJB1-PRKACA fusion has recently been reported in fibrolamellar carcinomas. To determine the specificity of this fusion and to develop routinely available clinical methods of detection, we developed an RT-PCR assay for paraffin-embedded tissues and a FISH probe for detection of the rearrangements of the PRKACA locus. We also developed an RNA in situ hybridization assay to assess expression levels of the total chimeric transcript and wild-type transcripts. A total of 106 primary liver tumors were studied by RT-PCR, including 26 fibrolamellar carcinomas (4 of which were metastases to the abdominal wall or lymph nodes), 25 conventional hepatocellular carcinomas, 25 cholangiocarcinomas, 25 hepatic adenomas, and 5 hepatoblastomas. RT-PCR was successful in 92% of tested fibrolamellar carcinoma cases (24/26) and the DNAJB1-PRKACA fusion transcript was found in all fibrolamellar carcinomas but not in other tumor types. FISH was tested in 19 fibrolamellar carcinomas and in 6 scirrhous hepatocellular carcinomas, which can closely mimic fibrolamellar carcinoma. Rearrangements of the PRKACA locus was seen in all 19 fibrolamellar carcinoma specimens, but in none of the scirrhous hepatocellular carcinomas. Finally, a RNA in situ hybridization strategy was positive in 7/7 successfully hybridized cases, and showed mRNA over-expression in all of the fibrolamellar carcinomas. In addition, the stromal cells embedded in the characteristic intratumoral fibrosis of fibrolamellar carcinomas and the background liver tissues were negative for the DNAJB1-PRKACA fusion by all tested methods. In conclusion, detection of DNAJB1-PRKACA is a very sensitive and specific finding in support of the diagnosis of fibrolamellar carcinoma.

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FGFR1 mRNA and Protein Expression, not Gene Copy Number, Predict FGFR TKI Sensitivity across All Lung Cancer Histologies

Cited by 145 publications

References 25 publications

Deep Sequencing in Conjunction with Expression and Functional Analyses Reveals Activation of FGFR1 in Ewing Sarcoma

Deep Sequencing in Conjunction with Expression and Functional Analyses Reveals Activation of FGFR1 in Ewing Sarcoma

High-Affinity Internalizing Human scFv-Fc Antibody for Targeting FGFR1-Overexpressing Lung Cancer

DNAJB1-PRKACA is specific for fibrolamellar carcinoma

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