FGFR1 Expression Levels Predict BGJ398 Sensitivity of FGFR1-Dependent Head and Neck Squamous Cell Cancers

Göke, Friederike; Franzen, Alina; Hinz, Trista K.; Marek, Lindsay A.; Yoon, Petros; Sharma, Rakesh Kumar; Bode, Maike; Maessenhausen, Anne Von; Lankat–Buttgereit, Brigitte; Göke, Antonia; Golletz, Carsten; Kirsten, Robert; Boehm, Diana; Vogel, Wenzel; Kleczko, Emily K.; Eagles, Justin R.; Hirsch, Fred R.; Bremen, Tobias Van; Bootz, Friedrich; Schroeck, Andreas; Kim, Jihye; Tan, Aik Choon; Jimeno, Antonio; Heasley, Lynn E.; Perner, Sven

doi:10.1158/1078-0432.ccr-14-3357

Cited by 77 publications

(66 citation statements)

References 34 publications

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“…Previous preclinical models demonstrated the efficacy of FGFR inhibitors PD173074, BGJ398, RO4383596 and AZ8010 in HNSCC (16)(17)(18)(19). Here we tested the activity of AZD4547 -a potent and selective pan-FGFR inhibitor currently in phase 2 clinical trial -in HNSCC cell lines.…”

Section: Discussionmentioning

confidence: 99%

“…Therapies inhibiting FGFR1 have shown to reduce HNSCC development in preclinical models and are currently being tested in clinical trials on solid tumors, including HNSCC (NCT01962532, NCT01004224, and NCT01948297; refs. [16][17][18][19]. Several multikinase inhibitors targeting FGFR and other kinases, for example, dovitinib and lucitanib, have already shown great therapeutic potential in clinical studies on FGFRaberrated breast cancer and various other advanced solid tumors (20,21).…”

Section: Introductionmentioning

confidence: 99%

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FGFR1 Is a Potential Prognostic Biomarker and Therapeutic Target in Head and Neck Squamous Cell Carcinoma

Koole

Brunen

Kempen

et al. 2016

Clinical Cancer Research

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Purpose: FGFR1 is a promising therapeutic target in multiple types of solid tumors, including head and neck squamous cell carcinoma (HNSCC). FGFR inhibitors have shown great therapeutic value in preclinical models. However, resistance remains a major setback. In this study, we have investigated the prognostic value of FGFR1 expression in HNSCC, the therapeutic relevance of targeting FGFR with AZD4547, and potential resistant mechanisms.Experimental Design: IHC and FISH were applied on tissue microarrays to investigate FGFR1 protein expression and FGFR1 gene copy numbers in 452 HNSCCs. The sensitivity of HNSCC cell lines to AZD4547, either as single or combination treatment with the EGFR inhibitor gefitinib, was assessed using long-term colony formation assays, short-term viability assays, and biochemical analysis.Results: FGFR1 protein overexpression occurred in 82% (36/ 44) of human papillomavirus (HPV)-positive HNSCC and 75% (294/392) of HPV-negative HNSCC and relates with poor overall survival and disease-free survival in HPV-negative HNSCC [HR, 3.07; 95% confidence interval (CI), 1.74-6.90; P ¼ 0.001 and HR, 1.53; 95% CI, 1.04-2.39; P ¼ 0.033]. Moreover, the FGFR1 gene was amplified in 3% (3/110) of HPV-negative HNSCC. Treatment of the high FGFR1-expressing cell line CCL30 with AZD4547 reduced cell proliferation and FGFR signaling. Two FGFR-amplified cell lines, SCC147 and BICR16, were resistant to AZD4547 treatment due to EGFR signaling. Combined AZD4547 and gefitinib treatment synergistically inhibited the proliferation of resistant cell lines.Conclusions: Here, we identify high FGFR1 expression as a candidate prognostic biomarker in HPV-negative HNSCC. Furthermore, we provide a rationale for treating FGFR1-expressing HNSCC with the FGFR inhibitor AZD4547 and for combining AZD4547 and gefitinib in FGFR inhibitor-resistant HNSCC patients. Clin Cancer Res; 22(15); 3884-93. Ó2016 AACR.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

FGFR1 Is a Potential Prognostic Biomarker and Therapeutic Target in Head and Neck Squamous Cell Carcinoma

Koole

Brunen

Kempen

et al. 2016

Clinical Cancer Research

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“…Preclinical analyses have linked FGFR1 overexpression to FGFR inhibitor sensitivity in HNSCC cell lines whereas results seem less clear for FGFR1 amplification as a predictive biomarker [31,32,62,63]. FGFR3 mutations, translocations, and mRNA expression have been identified mainly in HPV-positive HNSCC [6,19,64].…”

Section: Predictive Biomarkersmentioning

confidence: 99%

Targeted Therapy of Head and Neck Cancer

2016

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Head and neck squamous cell carcinoma (HNSCC) is one of the most common solid cancers worldwide. It is mainly caused by exposure to tobacco smoke and alcohol as well as infection with the human papilloma virus (HPV). The prognosis is poor, especially once it recurs or metastasizes. Current therapeutic options include surgery, radio- and chemotherapy. Epidermal growth factor receptor (EGFR) inhibitors are so far the only targeted agents that have been approved in head and neck cancer. Primary or secondary resistance is frequent or will eventually develop. Several driver mutations and other genomic aberrations have been described in HNSCC including EGFR overexpression and amplification. Yet, no predictive biomarkers for the application of EGFR inhibitors have been identified. Further targeted agents are in development for HNSCC, of which inhibitors of the PI3K pathway are the closest to clinical application. In recent years, the incidence of HPV-driven HNSCC has risen in Western countries. HPV-positive and -negative HNSCC are distinct molecular tumor entities, and consequences for targeted therapies have been discussed. This review looks at approved and investigational targeted treatment strategies as well as potential predictive biomarkers such as the HPV status to guide treatment.

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“…BGJ398 is a selective TKI that targets FGFRs1-3. This compound, either exclusively or in combination with other compounds, is being investigated in various phase II clinical trials of certain tumors [231,232]. The other two selective TKIs are pan (Greek meaning all) inhibitors i.e.…”

Section: Therapeutic Inhibition Of Fgfs-fgfrsmentioning

confidence: 99%