FGFR1/3 Tyrosine Kinase Fusions Define a Unique Molecular Subtype of Non–Small Cell Lung Cancer

Wang, Rui; Wang, Lei; Li, Yuan; Hu, Haichuan; Shen, Lei; Shen, Xueyan; Pan, Yunjian; Ye, Ting; Zhang, Yang; Luo, Xiangyang; Zhang, Yiliang; Pan, Bin; Li, Bin; Li, Hang; Zhang, Jie; Pao, William; Ji, Hongbin; Sun, Yihua; Chen, Haiquan

doi:10.1158/1078-0432.ccr-14-0284

Cited by 128 publications

(117 citation statements)

References 24 publications

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“…Fusions involving FGFR3 and TACC3 (transforming acidic coiled-coil containing protein 3) are found in 3% to 7% of glioblastomas (9-11), 3% to 6% of urothelial bladder carcinomas (14)(15)(16), and other tumor types at lower frequencies (12)(13)(14)(15). In mouse xenograft models, the induction of FGFR3--TACC3 expression in human astrocytes resulted in the development of gliomalike tumors (9).…”

Section: Dysregulation Of Fgfr Signaling In Human Malignanciesmentioning

confidence: 99%

Targeting FGFR Signaling in Cancer

Touat

Ileana

Postel-Vinay

et al. 2015

Clinical Cancer Research

424

369

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The fibroblast growth factor signaling pathway (FGFR signaling) is an evolutionary conserved signaling cascade that regulates several basic biologic processes, including tissue development, angiogenesis, and tissue regeneration. Substantial evidence indicates that aberrant FGFR signaling is involved in the pathogenesis of cancer. Recent developments of deep sequencing technologies have allowed the discovery of frequent molecular alterations in components of FGFR signaling among several solid tumor types. Moreover, compelling preclinical models have demonstrated the oncogenic potential of these aberrations in driving tumor growth, promoting angiogenesis, and conferring resistance mechanisms to anticancer therapies. Recently, the field of FGFR targeting has exponentially progressed thanks to the development of novel agents inhibiting FGFs or FGFRs, which had manageable safety profiles in early-phase trials. Promising treatment efficacy has been observed in different types of malignancies, particularly in tumors harboring aberrant FGFR signaling, thus offering novel therapeutic opportunities in the era of precision medicine. The most exciting challenges now focus on selecting patients who are most likely to benefit from these agents, increasing the efficacy of therapies with the development of novel potent compounds and combination strategies, and overcoming toxicities associated with FGFR inhibitors. After examination of the basic and translational research studies that validated the oncogenic potential of aberrant FGFR signaling, this review focuses on recent data from clinical trials evaluating FGFR targeting therapies and discusses the challenges and perspectives for the development of these agents. Clin Cancer Res; 21(12); 2684-94. Ó2015 AACR.

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Section: Dysregulation Of Fgfr Signaling In Human Malignanciesmentioning

confidence: 99%

Targeting FGFR Signaling in Cancer

Touat

Ileana

Postel-Vinay

et al. 2015

Clinical Cancer Research

424

369

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“…Total RNA samples were reverse transcribed into complementary DNA (cDNA) using RevertAid First Strand cDNA Synthesis Kit (Fermentas, St Leon-Rot, Germany). EGFR (exons [18][19][20][21][22], KRAS (exons 2-3), HER2 (exons 18-21), and BRAF (exons [11][12][13][14][15] were amplified by polymerase chain reaction (PCR) using cDNA. Amplified products were analyzed by direct dideoxynucleotide sequencing.…”

Section: Mutation Analysesmentioning

confidence: 99%

“…Amplified products were analyzed by direct dideoxynucleotide sequencing. ALK, RET, ROS1, and FGFR fusions were analyzed by qRT-PCR plus RT-PCR and confirmed by FISH as we had previously reported [13][14][15][16]. PCR products were directly sequenced in forward and reverse directions.…”

Section: Mutation Analysesmentioning

confidence: 99%

Former smokers with non‐small‐cell lung cancers: a comprehensive investigation of clinicopathologic characteristics, oncogenic drivers, and prognosis

et al. 2016

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The aim of this present investigation was to evaluate the clinicopathologic characteristics, oncogenic drivers, and prognosis of former smokers with non-smallcell lung cancer (NSCLC), and to compare them with those of the current and never smokers. This investigation was a single-institution retrospective study of 2289 NSCLC patients, who were classified as former, current, or never smokers. A collection was made of the clinicopathological characteristics, spectra of wellidentified driver genes and survival rates. The survival rates were compared using log-rank test, and independent prognostic factors, identified using Cox regression analysis. Of 2289 NSCLC patients, 257 (11.2%) were former smokers; 868 (37.9%), current smokers; and 1164 (50.9%), never smokers. Compared with the current, the former were characterized by older age at diagnosis (64.3y vs. 59.9y; P < 0.001), earlier TNM stage (stage I, 47.9% vs. 39.5%; P = 0.017), fewer solid predominance in adenocarcinomas (16.2% vs. 29.5%; P = 0.005), and more EGFR mutation (33.2% vs. 20.7%; P < 0.001) but less KRAS mutation (6.7% vs. 11.9%, P = 0.041). No statistically significant survival differences were observed between the former and current. However, the light former smokers presented favorable overall survival when compared with the light current and heavy former or current (the light former vs. the heavy former, P = 0.028; the light former vs. the light current, P = 0.048; and the light former vs. the heavy current, P = 0.048). Our findings suggest that the former smokers with NSCLCs can have distinctive clinicopathologic characteristics, oncogenic drivers, and prognosis, and they, especially the light former, can benefit from smoking cessation. Cancer Medicine Open Access 2118

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“…The FGFR family, comprising FGFR1, FGFR2, FGFR3 and FGFR4, play crucial roles in cancer development and are targets for dysregulation by amplification, point mutations, or translocation [5,9,10]. Amplified FGFR1 has been reported in 20% of SCCL and inhibition of the FGFR1 pathway with FGFR inhibitors was demonstrated to lead to significant tumor shrinkage, suggesting that FGFR inhibitors might be an effective therapeutic option in SCCL with FGFR1 amplification [11,12].…”

Section: Introductionmentioning

confidence: 99%

FGFR1 amplification and FGFR gene fusion in resected squamous cell carcinoma of the lung

Wang¹,

Liu²,

Wang³

et al. 2018

biomedicalresearch

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The objective of the present study was to investigate the clinicopathologic characteristics and prognostic role of FGFR1 amplification and FGFR fusion in patients with surgically resected squamous cell carcinoma of the lung (SCCL). Here, fluorescent in situ hybridization (FISH) was performed to detect FGFR1 amplification and reverse transcriptase polymerase chain reaction (RT-PCR) was used to screen 15 known FGFR fusion variants in 108 patients with surgically resected SCCL. All cases were also analyzed for EGFR, KRAS, HER2 and BRAF mutations. Clinical characteristics including age, sex, smoking status, stage, relapse-free survival (RFS) and overall survival (OS) were collected. Of 108 tumors screened, 14 (13.0%) FGFR1 amplification was found. There were 4 (3.7%) patients that harbored FGFR fusion including 2 BAG4-FGFR1 and 2 FGFR3-TACC3 fusion. Compared to the FGFR1 amplification negative group, patients with FGFR1 amplification were more likely to be smokers (100.0%, 14 of 14 patients, p=0.036), significantly associated with larger tumor (>3 cm) (88.2%, 13 of 14 patients, p=0.032). Patients with FGFR1 amplification had worse RFS (p=0.013) and OS (p=0.021) than those without FGFR1 amplification. There was no correlation between FGFR fusion and clinicopathologic characteristics. No significant difference in RFS or OS was found between patients with FGFR fusion and those without FGFR fusion. In conclusion, FGFR1 amplification and FGFR fusion occurred in 13.0% and 3.7% of patients with surgically resected SCCL, separately. FGFR1 amplification was correlated with poor prognosis and identified a distinct subset of SCCL with a higher prevalence among smokers with relative larger tumor (>3 cm). FGFR is a therapeutic target and patients with FGFR1 amplification or FGFR fusion may benefit from FGFR targeted therapy which needs further clinical investigation.

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FGFR1/3 Tyrosine Kinase Fusions Define a Unique Molecular Subtype of Non–Small Cell Lung Cancer

Cited by 128 publications

References 24 publications

Targeting FGFR Signaling in Cancer

Targeting FGFR Signaling in Cancer

Former smokers with non‐small‐cell lung cancers: a comprehensive investigation of clinicopathologic characteristics, oncogenic drivers, and prognosis

FGFR1 amplification and FGFR gene fusion in resected squamous cell carcinoma of the lung

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