scholarly journals STAT3 polymorphism associates with mTOR inhibitor-induced interstitial lung disease in patients with renal cell carcinoma

2022 ◽  
Author(s):  
Kazuhiro Yamamoto ◽  
Takeshi Ioroi ◽  
Kazuaki Shinomiya ◽  
Ayaka Yoshida ◽  
Kenichi Harada ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Interstitial Lung Disease ◽  
Lung Disease ◽  
Cell Carcinoma ◽  
Cell Lines ◽  
Renal Cell ◽  
Mtor Inhibitor ◽  
In Vitro Study ◽  
Primary Analysis

We evaluated the association of signal transducer and activator of transcription 3(STAT3) polymorphisms with the incidence of mammalian target of rapamycin (mTOR) inhibitor-induced interstitial lung disease (ILD) in patients with renal cell carcinoma (RCC). We also used lung-derived cell lines to investigate the mechanisms of this association. Japanese patients with metastatic RCC who were treated with mTORinhibitors were genotyped for the STAT3 polymorphism, rs4796793. We evaluated the association of the STAT3 genotype with the incidence of ILD and therapeutic outcome.In the 57 patients included in the primary analysis, the ILD rate within 140 days was significantly higher in patients with the CC genotype compared with those with other genotypes (77.8% versus 23.1%, odds ratio = 11.67, 95% confidential interval = 3.06–44.46). Meanwhile, there were no significant differences in progression-free survival ortime-to-treatment failure between the patients with the CC genotype and those with other genotypes. An in vitro study demonstrated that some lung-derived cell lines carrying the CC genotype exhibited an increase in the expression of mesenchymal markers, such as fibronectin, N-cadherin, and vimentin and decreases in E-cadherin, which is an epithelial marker associated with exposure to everolimus, although STAT3 expression and activity were not related to the genotype. In conclusion, the CCgenotype of the STAT3 rs4796793 polymorphism increases the risk of mTOR inhibitorinduced ILD, supporting its use as a predictive marker for RCC.

The role of ZNF395 in renal cell carcinoma proliferation, migration, and invasion.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 592-592 ◽  
Author(s):  
Chen Zhao ◽  
Christopher G. Wood ◽  
Jose A. Karam ◽  
Tapati Maity ◽  
Lei Wang
Keyword(s):  
Renal Cell Carcinoma ◽  
Tumor Growth ◽  
Cell Carcinoma ◽  
Cell Lines ◽  
Renal Cell ◽  
Migration And Invasion ◽  
Mrna Levels

592 Background: Zinc finger protein 395 (ZNF395) is frequently altered in several tumor types. However, the role of ZNF395 remains poorly studied in patients with clear cell renal cell carcinoma (RCC). In this study, we investigated the in vitro and in vivo role of ZNF395 in ccRCC. Methods: cBioPortal For Cancer Genomics was used to correlate the expression of ZNF395 with RCC patient clinical, pathological and molecular profiles. ZNF395 protein and mRNA levels were studied in several RCC cell lines in vitro. Subsequently, ZNF395 knockdown was performed in 786-O and UMRC3 RCC cells and overexpression was done in Caki-1 and 769-P RCC cells. We then evaluated ZNF395 modulation in these cell lines by in vitro MTT, migration and invasion assays. Finally, we studied the effect of ZNF395 knockout and overexpression in vivo using SCID xenograft models. Results: Patients with higher expression of ZNF395 experienced longer disease-free survival and overall survival. Using in vitro models, we confirmed that knockdown of ZNF395 decreased ZNF395 expression, and increased proliferation, migration and invasiveness of 786-O and UMRC3, while overexpression of ZNF395 increased ZNF395 expression, and reduced proliferation, migration and invasiveness of Caki-1 and 769-P. Using in vivo mouse models, knockdown of ZNF395 expression in 786-O promoted tumor growth while its overexpression in Caki-1 resulted in tumor growth inhibition. We are currently performing experiments to understand the process by which ZNF395 regulates ccRCC pathogenesis. Conclusions: Our data support the role of ZNF395 as an important tumor suppressor gene in the pathogenesis of RCC.

scholarly journals Inhibition of the CDK4/6-Cyclin D-Rb Pathway by Ribociclib Augments Chemotherapy and Immunotherapy in Renal Cell Carcinoma

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Dehong Chen ◽  
Xiaosong Sun ◽  
Xuejun Zhang ◽  
Jun Cao
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Cell Lines ◽  
Renal Cell ◽  
Target Genes ◽  
Standard Of Care ◽  
Cyclin D ◽  
Rb Pathway

Renal cell carcinoma (RCC) is the most aggressive type of genitourinary cancer and is resistant to current therapies. Identifying drugs that enhance the efficacy of RCC standard-of-care drugs at sublethal concentrations is an alternative therapeutic strategy. Ribociclib is an orally available cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor that is approved for the treatment of breast cancer. In this work, we demonstrate that ribociclib at clinically achievable concentrations inhibits proliferation of 7 out of 9 tested RCC cell lines, with IC50 range from 76 to 280 nM. In addition, ribociclib induces apoptosis of RCC cells, but with less potency compared to its antiproliferative activity. The combination of ribociclib with chemotherapeutic or immunotherapeutic agents is synergistic in RCC cell lines. Of note, ribociclib demonstrates selective anti-RCC activity by sparing normal kidney cells and fibroblast cells. Consistent with the in vitro findings, ribociclib inhibits RCC growth at the dosage that does not lead to toxicity in mice and enhances the in vivo efficacy of RCC standard-of-care drugs. Mechanistically, we show that ribociclib remarkably inhibits phosphorylation of retinoblastoma protein (Rb) at various sites, leading to the suppression of transcription of E2F target genes in RCC cells. Our findings clearly demonstrate the potency and selectivity of ribociclib in RCC preclinical models, via inhibition of the CDK4/6-cyclin D/Rb pathway. Our findings support a clinical trial for the combination of ribociclib with chemo/immunotherapy in RCC.

Pazopanib-associated interstitial lung disease in a patient with renal cell carcinoma

2020 ◽  
Vol 13 (7) ◽  
pp. e235177 ◽  
Author(s):  
Yukinori Harada ◽  
Shintaro Kakimoto ◽  
Taro Shimizu
Keyword(s):  
Renal Cell Carcinoma ◽  
Interstitial Lung Disease ◽  
Lung Disease ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Kinase Inhibitor ◽  
Lung Metastases ◽  
Soft Tissue Sarcomas ◽  
Positive Pressure ◽  
Non Invasive

Pazopanib is a multi-targeted tyrosine kinase inhibitor, which is indicated for use in patients with advanced renal cell carcinoma or advanced soft-tissue sarcomas. Although rare, interstitial lung disease has been reported as among the adverse sequelae of pazopanib therapy. We report the case of a 75-year-old man who developed interstitial lung disease during treatment with pazopanib for renal cell carcinoma with multiple lung metastases. The patient presented with dry cough and new-onset fatigue 3 months after initiation of pazopanib. He had mild hypoxia with bilateral ground-glass opacities on chest CT. He was treated with antibiotics for presumptive pneumonia, but his respiratory status rapidly deteriorated, and he required non-invasive positive pressure ventilation. He recovered on discontinuation of pazopanib and systemic steroids. Clinicians should recognise that interstitial lung disease can occur in patients who are undergoing treatment with pazopanib.

Incidence and outcome of interstitial lung disease (ILD) with everolimus treatment for metastatic renal cell carcinoma.

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 427-427
Author(s):  
Fumiya Hongo ◽  
Masakatsu Oishi ◽  
Takashi Ueda ◽  
Yasunori Kimura ◽  
Terukazu Nakamura ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Interstitial Lung Disease ◽  
Adverse Events ◽  
Lung Disease ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Progression Free Survival ◽  
Intermediate Risk ◽  
Free Survival

427 Background: Interstitial lung disease (ILD) is known as one of the adverse events during treatment with everolimus for metastatic renal cell carcinoma (mRCC). Methods: We retrospectively assessed the incidence and outcome of ILD in mRCC patients treated with everolimus. From April 2010 to August 2012, 25 cases were treated with everolimus after failure of one or two TKIs in our institute. All adverse events were graded in accordance with NCI CTCAE, version 3.0. Results: A total of 25 patients received treatment with everolimus. They included 18 male and 7 female patients ranging in age from 21 to 84 years (median 62). According to MSKCC risk criteria, 6 cases were at favorable risk, 16 cases were at intermediate risk, and 3 cases were at poor risk. Median treatment term was 4 months (range 2-17 months). SD was in 19 cases and PD was in 6 cases. Progression free survival was 3.5 months and overall survival was 12 months. ILD was found in 7 cases (28%). 1 was G1, 5 were G2 and 1 was G3. Corticosteroid therapy was initiated in 3 cases. In 5 of 7 ILD cases, everolimus was re-challenged. In our series, patients with ILD showed significantly better progression free survival than those without ILD (PFS was 8 months vs. 3 months. Log-rank, p < 0.001). There were no significant different between the 2 groups in over all survival (12 months in patients with ILD vs. 10 months in patients without ILD. Log-rank, NS). Conclusions: Everolimus appears to be effective and well-tolerated in our institute. Re-challenge of everolimus was feasible after improving of everolimus-induced ILD in cases of grade 1-2.

Long Noncoding RNA LINC00460 Facilitates the Proliferation and Metastasis of Renal Cell Carcinoma via PI3K/AKT Signaling Pathway

2021 ◽  
Author(s):  
Feng-Juan Zhou ◽  
Sen Meng ◽  
Hongmei Yong ◽  
Ping-Fu Hou ◽  
Min-Le Li ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Cell Lines ◽  
Renal Cell ◽  
Noncoding Rna ◽  
Underlying Mechanism ◽  
The Cancer Genome Atlas ◽  
Akt Pathway

Abstract Renal cell carcinoma (RCC) is one of the most prevalent cancers. Long noncoding RNAs (LncRNAs) have been indicated as a mediator acted in tumorigenesis of RCC. However, the mechanism of LINC00460 on RCC is yet to be investigated. This study aimed to investigate the potential function of LINC00460 and underlying mechanism of RCC. We detected LINC00460 expression in RCC tissues and the prognosis in RCC patients using Gene Expression Profiling Interactive Analysis (GEPIA) website and The Cancer Genome Atlas (TCGA) database. LINC00460 level in normal renal cell line and RCC cell lines were detected by quantitative real-time polymerase chain reaction (qRT-PCR). We study the effects of LINC00460 on proliferation, migration, invasion, apoptosis in RCC cells lines using a series of in vivo and in vitro experiments. RNA sequencing (RNA-seq) analysis for the whole transcriptome was applied to searching potential LINC00460 related signal pathway in RCC. We identified the significant up-regulated expression level of LINC00460 in RCC tissues and cell lines. Elevated LINC00460 was correlated with shorter survival of RCC patients. Overexpression of LINC00460 promoted cell viability, proliferation, invasion and migration, while down-regulation of LINC00460 exerted inhibitory effect on these activities. We crucially identified that LNC00460 promotes development of RCC by influencing the PI3K/AKT pathway. Knockdown of LNC00460 decreased the phosphorylation of AKT and mTOR. The key finding of our study provided a new evidence suggesting that LINC00460 functions as an oncogene in RCC pathogenesis by mediating the PI3K/AKT pathway, which may provide a new target for the treatment of RCC.

scholarly journals Anti-tumor effect of ribavirin in combination with interferon-α on renal cell carcinoma cell lines in vitro

2014 ◽  
Vol 14 (1) ◽  
pp. 63 ◽  
Author(s):  
Lichen Teng ◽  
Dexin Ding ◽  
Yongsheng Chen ◽  
Hongshuang Dai ◽  
Guobin Liu ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Cell Lines ◽  
Renal Cell ◽  
Carcinoma Cell ◽  
Interferon Α ◽  
Renal Cell Carcinoma Cell ◽  
Carcinoma Cell Lines
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