FGF19 amplification reveals an oncogenic dependency upon autocrine FGF19/FGFR4 signaling in head and neck squamous cell carcinoma

Gao, Lixia; Lang, Liwei; Zhao, Xin; Shay, Chloe; Shull, Austin Y.; Teng, Yong

doi:10.1038/s41388-018-0591-7

Cited by 58 publications

(59 citation statements)

References 34 publications

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“…FGF19 is highly amplified in lung squamous cell carcinoma, which ranks the fourth in the frequency in all examined cancer types from the TCGA Pan-Cancer cohort [16]. By quantitative RT-PCR analysis, we observed in our cohort [7] that FGF19 gene copy number increased in 9 out of 37 samples, along with increased copy number of three other genes CCND1, FGF3 and FGF4 (Fig.…”

Section: Fgf19 Is Upregulated In Lsq Tissues and Is A Poor Prognosticmentioning

confidence: 60%

“…FGF19 also protects hepatocellular carcinoma cells against endoplasmic reticulum (ER) stress [12]. Furthermore, FGF19 is critical for the progression of breast cancer [13], prostate cancer [14,15], head and neck squamous cell carcinoma [16] and thyroid cancer [17]. An anti-FGF19 monoclonal antibody 1A6 acting to block the interaction of FGF19 with its receptor FGFR4 could inhibit the colon tumor xenografts in vivo [18].…”

Section: Introductionmentioning

confidence: 99%

“…The FGF19/FGFR4 axis has also been reported to induce mTORC1 and ERK pathways to converge on S6 in hepatoma cells and in head and neck squamous cell carcinoma (HNSCC) [16,26]. Several PI3K/AKT/mTOR pathway inhibitors have shown antitumor activity in preclinical models of NSCLC [27].…”

Section: Introductionmentioning

confidence: 99%

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Enhanced autocrine FGF19/FGFR4 signaling drives the progression of lung squamous cell carcinoma, which responds to mTOR inhibitor AZD2104

Fan

Han

et al. 2020

Oncogene

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Lung cancer occurrence and associated mortality ranks top in all countries. Despite the rapid development of targeted and immune therapies, many patients experience relapse within a few years. It is urgent to uncover the mechanisms that drive lung cancer progression and identify novel molecular targets. Our group has previously identified FGF19 as a prognostic marker and potential driver gene of lung squamous cell carcinomas (LSQ) in Chinese smoking patients. However, the underlying mechanism of how FGF19 promotes the progression of LSQ remains unclear. In this study, we characterized and confirmed that FGF19 serves as an oncogenic driver in LSQ development and progression, and reported that the amplification and high expression of FGF19 in LSQ was significantly associated with poor overall and progression-free survival. A higher serum level of FGF19 was found in lung cancer patients, which could also serve as a novel diagnostic index to screen lung cancer. Overproduction of FGF19 in LSQ cells markedly promoted cell growth, progression and metastasis, while downregulating FGF19 effectively inhibited LSQ progression in vitro and in vivo. Moreover, downregulating the receptor FGFR4 was also effective to suppress the growth and migration of LSQ cells. Since FGF19 could be induced by smoking or endoplasmic reticulum stress, to tackle the more malignant FGF19-overproducing LSQ, we reported for the first time that inhibiting mTOR pathway by using AZD2014 was effective and feasible. These findings have offered a new strategy by using anti-FGF19/FGFR4 therapy or mTOR-based therapy in FGF19-driven LSQ.

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Section: Fgf19 Is Upregulated In Lsq Tissues and Is A Poor Prognosticmentioning

confidence: 60%

Section: Introductionmentioning

confidence: 99%

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Enhanced autocrine FGF19/FGFR4 signaling drives the progression of lung squamous cell carcinoma, which responds to mTOR inhibitor AZD2104

Fan

Han

et al. 2020

Oncogene

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“…Compared to the other three FGFR family members, the function of the FGFR4 signaling pathway in cancer is less well-characterized. Recently, it has been reported that the activation of FGF19-FGFR4 signaling is closely associated with cancer development and progression Chen et al, 2019), suggesting that FGF19-FGFR4 might be an attractive target for effective anticancer therapeutics (Schadt et al, 2018;Gao et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Dissecting the Role of the FGF19-FGFR4 Signaling Pathway in Cancer Development and Progression

Liu

Cao

Cai

et al. 2020

Front. Cell Dev. Biol.

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“…OSCC is frequently associated with poor prognosis due to the high risk of cervical lymph node metastasis even when the tumors are small (T1 and T2). We have generated the orthotopic mouse model for tongue tumors by injection of OSCC cells to NSG mice tongue [11,14]. However, increased tumor size in the tongue could stop mice from eating and tumor-bearing mice often reach a moribund state before cervical or distant metastasis is established from tongue primary tumors.…”

Section: Discussionmentioning

confidence: 99%

Circumventing AKT-Associated Radioresistance in Oral Cancer by Novel Nanoparticle-Encapsulated Capivasertib

Lang

Lam

Chen

et al. 2020

Cells

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Background: Development of radioresistance in oral squamous cell carcinoma (OSCC) remains a significant problem in cancer treatment, contributing to the lack of improvement in survival trends in recent decades. Effective strategies to overcome radioresistance are necessary to improve the therapeutic outcomes of radiotherapy in OSCC patients. Methods: Cells and xenograft tumors were irradiated using the Small Animal Radiation Research Platform. AKT inhibitor capivasertib (AZD5363) was encapsulated into cathepsin B-responsible nanoparticles (NPs) for tumor-specific delivery. Cell viability was measured by alamarBlue, cell growth was determined by colony formation and 3D culture, and apoptosis was assessed by flow cytometry with the staining of Fluorescein isothiocyanate (FITC) Annexin V and PI. An orthotopic tongue tumor model was used to evaluate the in vivo therapeutic effects. The molecular changes induced by the treatments were assessed by Western blotting and immunohistochemistry. Results: We show that upregulation of AKT signaling is the critical mechanism for radioresistance in OSCC cells, and AKT inactivation by a selective and potent AKT inhibitor capivasertib results in radiosensitivity. Moreover, relative to irradiation (IR) alone, IR combined with the delivery of capivasertib in association with tumor-seeking NPs greatly enhanced tumor cell repression in 3D cell cultures and OSCC tumor shrinkage in an orthotopic mouse model. Conclusions: These data indicate that capivasertib is a potent agent that sensitizes radioresistant OSCC cells to IR and is a promising strategy to overcome failure of radiotherapy in OSCC patients.

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FGF19 amplification reveals an oncogenic dependency upon autocrine FGF19/FGFR4 signaling in head and neck squamous cell carcinoma

Cited by 58 publications

References 34 publications

Enhanced autocrine FGF19/FGFR4 signaling drives the progression of lung squamous cell carcinoma, which responds to mTOR inhibitor AZD2104

Enhanced autocrine FGF19/FGFR4 signaling drives the progression of lung squamous cell carcinoma, which responds to mTOR inhibitor AZD2104

Dissecting the Role of the FGF19-FGFR4 Signaling Pathway in Cancer Development and Progression

Circumventing AKT-Associated Radioresistance in Oral Cancer by Novel Nanoparticle-Encapsulated Capivasertib

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