Increased FGFR1 copy number in lung squamous cell carcinomas

Sasaki, Hidefumi; Shitara, Masayuki; Yokota, Keisuke; Hikosaka, Yu; Moriyama, Satoru; Yano, Motoki; Fujii, Yoshitaka

doi:10.3892/mmr.2011.715

Cited by 17 publications

(29 citation statements)

References 24 publications

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“…Clearly, discovering novel oncogenic drivers in NSCLC is paramount for improving current therapy. Recently, the fibroblast growth factor receptor 1 (FGFR1) was identified to be frequently amplified in squamous cell lung cancer (>20% of cases) (4,5) as well as in small-cell lung cancer (6% of cases) (6). However, it is still unknown whether these cells are completely addicted to FGFR1 signaling and whether pharmacologically targeting FGFR1 is effective in inhibiting cancer growth.…”

Section: Introductionmentioning

confidence: 99%

Novel FGFR inhibitor ponatinib suppresses the growth of non-small cell lung cancer cells overexpressing FGFR1

et al. 2013

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Abstract. Lung cancer is still the leading cause of cancerrelated deaths worldwide. Identifying new oncogenic drivers and developing efficient inhibitors through molecular targeting approaches are crucial for improving therapies. The aim of this study was to investigate whether targeting fibroblast growth factor receptor 1 (FGFR1) with ponatinib inhibits the cell growth in both established and primary lung cancer cells overexpressing FGFR1. Eighty-eight non-small cell lung cancer (NSCLC) and paired normal tissue specimens were analyzed by real-time RT-PCR for FGFR1 gene expression. We identified four cell lines and two newly established primary lung cancer cultures that showed high FGFR1 expression levels, and evaluated the effect of the novel FGFR1 inhibitor ponatinib on cell growth. Approximately 50% (30 out of 59) NSCLC specimens expressed FGFR1 >2-fold compared with their adjacent normal counterparts using quantitative RT-PCR. Ponatinib treatment of established NSCLC cell lines expressing higher levels of FGFR1 resulted in marked cell growth inhibition and suppression of clonogenicity. This growth inhibition was associated with inactivation of FGFR1 and its downstream targets. FGFR1 knockdown by shRNA achieved similar results when compared to treatment with ponatinib. Furthermore, ponatinib was able to significantly inhibit the growth of primary lung cancer cultures in vitro. Our data indicate that pharmacological inhibition of FGFR1 kinase activity with ponatinib may be effective for the treatment of lung cancer patients whose tumors overexpress FGFR1.

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Section: Introductionmentioning

confidence: 99%

Novel FGFR inhibitor ponatinib suppresses the growth of non-small cell lung cancer cells overexpressing FGFR1

et al. 2013

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“…We divided our patient cohort into these groups as other studies investigating FGFR1 amplification in non-small cell lung carcinomas include patients with squamous cell carcinoma only 21,22,27 and patients with squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. [23][24][25][26] In addition, we found no significant difference in overall survival in surgically radically treated patients stratified by stage and FGFR1 amplification status. Considering statistically significant results only, most studies 9,21,[24][25][26] reported a lack of a significant relationship between survival and FGFR1 amplification status, in line with our findings.…”

Section: Discussionmentioning

confidence: 69%

“…[23][24][25][26] In addition, we found no significant difference in overall survival in surgically radically treated patients stratified by stage and FGFR1 amplification status. Considering statistically significant results only, most studies 9,21,[24][25][26] reported a lack of a significant relationship between survival and FGFR1 amplification status, in line with our findings. However, two studies did detect an effect of FGFR1 amplification on survival with Kim et al 22 reporting significantly greater risk of recurrence and death for patients with FGFR1-amplified squamous cell carcinoma, whereas Tran et al 23 reported a nonsignificant direction of effect toward longer overall survival for patients with FGFR1-amplified tumors in univariate analysis (P ¼ 0.14), which became significant on multivariate analysis (HR 0.6, P ¼ 0.02).…”

Section: Discussionmentioning

confidence: 69%

“…FISH has been the most frequently used method to detect FGFR1 amplification status, 9,10,21,22,[25][26][27] although alternative methods such as real-time polymerase chain reaction 24 and SISH 23 have also been used. SISH has several advantages over FISH including automation, use of bright-field microscopes in contrast to expensive FISH microscopes, signal permanence, and easier histologic comparison.…”

Section: Discussionmentioning

confidence: 99%

“…13,14 FGFR1 amplification has recently been reported by members of our group in oral squamous cell carcinoma, 15 but it has also been described in esophageal squamous cell carcinoma, ovarian cancer, bladder cancer, prostate cancer, and rhabdomyosarcoma. [16][17][18][19][20] Subsequent to the landmark initial studies, 9,10 other groups [21][22][23][24][25][26][27] have investigated FGFR1 amplification in non-small cell lung carcinoma, using different definitions of FGFR1 amplification generally utilizing FISH, but there have been reports utilizing silver in situ hybridization (SISH) 23 and real-time polymerase chain reaction. 24 The frequency of FGFR1 amplification in squamous cell carcinoma and its potential as an actionable molecular target highlight the importance of not only defining amplification but also determining the most reliable and reproducible method to detect its presence, as well as assessing which tumor subtypes to test.…”

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confidence: 99%

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Prevalence, morphology, and natural history of FGFR1-amplified lung cancer, including squamous cell carcinoma, detected by FISH and SISH

Russell

Young

et al. 2014

Modern Pathology

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The aim of this study was to investigate the prevalence of fibroblast growth factor receptor 1 (FGFR1) amplification by fluorescence in situ hybridization (FISH) in a lung cancer patient cohort and to correlate results with morphology, silver in situ hybridization (SISH), and patient outcome. FGFR1 FISH and SISH were performed in 406 and 385 lung cancer cases, respectively, and the results were compared. High-level FGFR1 amplification was defined as the ratio of FGFR1/centromere 8 Z2, or tumor cell percentage with Z15 signals Z10%, or average number of signals/tumor cell nucleus Z6. Low-level amplification was defined as tumor cell percentage with Z5 signals Z50%. Of 406 tumors tested, there were 191 squamous cell carcinomas, 28 carcinomas with focal squamous morphology, 24 large cell carcinomas with squamous immunoprofile, 115 adenocarcinomas, 17 neuroendocrine tumors, and 31 carcinomas without squamous morphology or immunoprofile. FGFR1 FISH was assessable in 368 tumors, with FGFR1 amplification identified in 50, including 48 tumors with either squamous morphology or immunoprofile (48 of 225, 21.3%), and two 'marker-null' tumors without squamous or glandular morphology or immunoprofile (2 of 143, 1.4%; Po0.0001). FGFR1 SISH was assessable in 347 tumors. All 46 FGFR1 FISH-amplified tumors with tumor available for testing showed amplification with SISH, while all other tumors were negative. There was no relationship between FGFR1 amplification status and disease-free (P ¼ 0.88, HR ¼ 1.04, 95% confidence interval (CI) ¼ 0.67-1.60) or overall survival (P ¼ 0.97, HR ¼ 1.01, 95% CI ¼ 0.65-1.58) in surgically radically treated patients with tumors with any squamous morphology or immunoprofile. FGFR1 amplification is a common abnormality in tumors with any squamous morphology or immunoprofile, but it is also present in 'marker-null' tumors. The results of FGFR1 SISH showed 1:1 correlation with the results of FGFR1 FISH, indicating that SISH may be an alternative method to detect FGFR1 amplification. No relationship was detected between patient outcome and FGFR1 amplification. Keywords: amplification; fibroblast growth factor receptor 1; squamous cell lung carcinomaIn Australia in 2009, lung cancer was the fifth most commonly diagnosed cancer, but it was the most common cause of cancer deaths for both men and women. 1 Approximately 85% of lung cancers are of non-small-cell carcinoma type, the subtypes of which are in reducing order of frequency: adenocarcinoma, squamous cell carcinoma, and large cell carcinoma, the latter being a morphologic diagnosis

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Fibroblast growth factor signaling and inhibition in non‐small cell lung cancer and their role in squamous cell tumors

Salgia

2014

Cancer Medicine

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With the introduction of targeted agents primarily applicable to non-small cell lung cancer (NSCLC) of adenocarcinoma histology, there is a heightened unmet need in the squamous cell carcinoma population. Targeting the angiogenic fibroblast growth factor (FGF)/FGF receptor (FGFR) signaling pathway is among the strategies being explored in squamous NSCLC; these efforts are supported by growth-promoting effects of FGF signaling in preclinical studies (including interactions with other pathways) and observations suggesting that FGF/FGFR-related aberrations may be more common in squamous versus adenocarcinoma and other histologies. A number of different anti-FGF/FGFR approaches have shown promise in preclinical studies. Clinical trials of two multitargeted tyrosine kinase inhibitors are restricting enrollment to patients with squamous NSCLC: a phase I/II trial of nintedanib added to first-line gemcitabine/cisplatin and a phase II trial of ponatinib for previously treated advanced disease, with the latter requiring not only squamous disease but also a confirmed FGFR kinase amplification or mutation. There are several ongoing clinical trials of multitargeted agents in general NSCLC populations, including but not limited to patients with squamous disease. Other FGF/FGFR-targeted agents are in earlier clinical development. While results are awaited from these clinical investigations in squamous NSCLC and other disease settings, additional research is needed to elucidate the role of FGF/FGFR signaling in the biology of NSCLC of different histologies.

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Increased FGFR1 copy number in lung squamous cell carcinomas

Cited by 17 publications

References 24 publications

Novel FGFR inhibitor ponatinib suppresses the growth of non-small cell lung cancer cells overexpressing FGFR1

Novel FGFR inhibitor ponatinib suppresses the growth of non-small cell lung cancer cells overexpressing FGFR1

Prevalence, morphology, and natural history of FGFR1-amplified lung cancer, including squamous cell carcinoma, detected by FISH and SISH

Fibroblast growth factor signaling and inhibition in non‐small cell lung cancer and their role in squamous cell tumors

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