Therapeutic Targeting of TFE3/IRS-1/PI3K/mTOR Axis in Translocation Renal Cell Carcinoma

Damayanti, Nur P.; Budka, Justin A.; Khella, Heba; Ferris, Mary W.; Ku, Sheng-Yu; Kauffman, Eric; Wood, Anthony C.; Ahmed, Khunsha; Chintala, Venkata Nithinsai; Adelaiye-Ogala, Remi; Elbanna, May; Orillion, Ashley; Chintala, Sreenivasulu; Kao, Chinghai; Linehan, W. Marston; Yousef, George M.; Hollenhorst, Peter C.; Пили, Роберто

doi:10.1158/1078-0432.ccr-18-0269

Cited by 61 publications

(47 citation statements)

References 51 publications

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“…Accompanying with the recent hunt for the genetics causes of KC, such as TFE3, TFEB, or MITF gene fusions, the overall genetic alterations of PI3K/AKT pathway comprising PIK3CA (2.8%), PIK3R1 (0.4%), PIK3R2 (0.3%), AKT1 (0.5%), AKT2 (0.6%) and PTEN (4%, Table 1) are captured in KC. To a further extent, PI3K/AKT/mTOR is identified as a highly enriched pathway in translocation RCC with TFE3 fusion (TFE3-tRCC) by miRNA microarray analysis [258]. Besides that PIK3R1 regulates EMT and stem-like phenotype of RCC cells through the AKT/GSK3β/CTNNB1 pathway [259], FoxO, PKCε, TPD52, NOTCH1, ETS2, miR-19b, -122, -182, -193a-3p, -195, and -224, as well as LncRNA MALAT1, TP73-AS1 and HOTTIP modulate proliferation, apoptosis, invasion, metastasis, or EMT via PI3K/ AKT pathway [260][261][262][263][264][265][266][267][268][269][270][271][272].…”

Section: Dysregulation Of the Pi3k/akt Pathway In The Genitourinary Smentioning

confidence: 99%

Role of PI3K/AKT pathway in cancer: the framework of malignant behavior

et al. 2020

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Given that the PI3K/AKT pathway has manifested its compelling influence on multiple cellular process, we further review the roles of hyperactivation of PI3K/AKT pathway in various human cancers. We state the abnormalities of PI3K/AKT pathway in different cancers, which are closely related with tumorigenesis, proliferation, growth, apoptosis, invasion, metastasis, epithelial-mesenchymal transition, stem-like phenotype, immune microenvironment and drug resistance of cancer cells. In addition, we investigated the current clinical trials of inhibitors against PI3K/AKT pathway in cancers and found that the clinical efficacy of these inhibitors as monotherapy has so far been limited despite of the promising preclinical activity, which means combinations of targeted therapy may achieve better efficacies in cancers. In short, we hope to feature PI3K/ AKT pathway in cancers to the clinic and bring the new promising to patients for targeted therapies.

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Section: Dysregulation Of the Pi3k/akt Pathway In The Genitourinary Smentioning

confidence: 99%

Role of PI3K/AKT pathway in cancer: the framework of malignant behavior

et al. 2020

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“…Translocation renal cell carcinomas (tRCC) encompass a diverse group of renal tumors associated with various gene fusions involving MiT (microphtalmia‐associated transcription factor) family members such as TFE3 and TFEB genes . Of patients with renal tRCCs, one third are children, one sixth are younger than 50, and 0.6% to 4% are older adults, although adult cases outnumber pediatric cases due the much greater incidence of renal cell carcinoma (RCC) in adults . In addition to affecting younger patients, tRCCs often present as high stage advanced disease and have poor outcomes that are likely similar to that of clear cell RCCs .…”

Section: Introductionmentioning

confidence: 99%

“…In addition to affecting younger patients, tRCCs often present as high stage advanced disease and have poor outcomes that are likely similar to that of clear cell RCCs . Accurate diagnosis of tRCC is required for prognosis and guiding clinical management since these tumors are poorly responsive to targeted therapies developed for conventional RCC, but may benefit from novel treatment strategies such as dual PIK3/mTOR inhibition, siRNA‐mediated TFE3 silencing, and MET inhibitors . Moreover, despite clinically aggressive manifestations, tRCC have low mutational burden suggesting poor response to immunotherapy …”

Section: Introductionmentioning

confidence: 99%

Gene fusion analysis in renal cell carcinoma by FusionPlex RNA‐sequencing and correlations of molecular findings with clinicopathological features

Tretiakova

Wang

et al. 2019

Genes Chromosomes & Cancer

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Translocation renal cell carcinoma (tRCC) affects younger patients and often presents as advanced disease. Accurate diagnosis is required to guide clinical management.Here we evaluate the RNA-sequencing FusionPlex platform with a 115-gene panel including TFE3 and TFEB for tRCC diagnosis and correlate molecular findings with clinicopathological features. We reviewed 996 consecutive RCC cases from our institution over the preceding 7 years and retrieved 17 cases with histological and immunohistochemical features highly suggestive of either TFE3 (n = 16) or TFEB (n = 1).Moderate to strong labeling for TFE3 was present in 15 cases; two cases with weak TFE3 expression were melan-A or cathepsin-K positive. RNA-sequencing detected gene rearrangements in eight cases: PRCC-TFE3 (3), ASPSCR1-TFE3 (2), LUC7L3-TFE3(1), SFPQ-TFE3 (1), and a novel SETD1B-TFE3 (1). FISH assays of 11 tumors verified six positive cases concordant with FusionPlex analysis results. Two other cases were confirmed by RT-PCR. FusionPlex was superior to FISH by providing precise breakpoints for tRCC-related genes in a single assay and allowing identification of both known and novel fusion partners, thereby facilitating clinicopathological correlations as fusion partners can influence tumor appearance, immunophenotype, and behavior. Cases with partner genes PRCC and novel partner SETD1B were associated with prominent papillary architecture while cases with partner genes ASPSCR1 and LUC7L3 were associated with a predominantly nested/alveolar pattern. The case with SFPQ-TFE3 fusion was characterized by biphasic morphology mimicking TFEB-like translocation RCC. We recommend FusionPlex analysis of RCC in patients under age 50 or when the histologic appearance suggests tRCC. K E Y W O R D S anchored multiplex PCR (AMP), FusionPlex, MiT family, RNA-seq, translocation renal cell carcinoma

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“…Insulin receptor substrate 1 (IRS-1) is an important molecule of the insulin signal transduction pathway and plays multiple varieties of biological regulations in insulin metabolism [ 14 , 15 ]. Recently, some studies showed that IRS-1 was associated with the occurrence and development of several different tumors, including HCC, lung cancer, breast cancer, pancreatic cancer, ovarian cancer, and renal cell carcinoma [ 16 – 19 ]. Tanaka et al analyzed the IRS-1 gene expression in 22 human HCC tumors and adjacent noninvolved liver tissues and found that approximately 40% of them had enhanced (>200%) expression compared with paracancerous tissues [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

Expression and Significance of Insulin Receptor Substrate 1 in Human Hepatocellular Carcinoma

Gao

Zhang

et al. 2020

Disease Markers

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Background. Insulin receptor substrate 1 (IRS-1) is an important molecule of the insulin signal transduction pathway and has been associated with the occurrence and development of many tumors, including hepatocellular carcinoma (HCC). Our study was designed to determine the expression and significance of IRS-1 in human HCC. Methods. Two hundred and forty specimens were drawn from 140 patients, including 100 HCC tissues and 100 paracancerous (PC) tissues from 100 HCC patients, 20 liver cirrhosis (LC) tissues from 20 LC patients, and 20 chronic hepatitis (CH) tissues from 20 CH patients. Baseline and pathological characteristics were included, and the expression of IRS-1 was examined by immunohistochemical (IHC) staining. Binary logistic regression model calculation was used for multivariate analysis. Results. The total positive rates of IRS-1 expression were 41.0%, 17.0%, 15.0%, and 10.0% in HCC, PC, LC and CH tissues, respectively. IRS-1-positive signals were brown in color and located in the nucleus and cytoplasm. Compared with PC, LC, and CH tissues, a significantly increased expression was observed in human HCC tissues (P<0.001, P=0.028, and P=0.008). Eight of the total 240 specimens had the strong immunostaining of IRS-1 expression, and all of them were HCC tissues. After control of the age, gender, and HBV and HCV infection, IRS-1 expression was independently associated with the diagnosis of HCC (OR 6.60, 95% CI 2.243-19.425, P=0.001). Conclusions. Positive expression of IRS-1 in HCC was increased significantly and may play an important role in the occurrence and development of human HCC.

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Therapeutic Targeting of TFE3/IRS-1/PI3K/mTOR Axis in Translocation Renal Cell Carcinoma

Abstract: These results identify TFE3/IRS-1/PI3K/AKT/mTOR as a potential dysregulated pathway in TFE3-tRCC, and suggest a therapeutic potential of vertical inhibition of this axis by using a dual PI3K/mTOR inhibitor for patients with TFE3-tRCC.

Cited by 61 publications

References 51 publications

Role of PI3K/AKT pathway in cancer: the framework of malignant behavior

Role of PI3K/AKT pathway in cancer: the framework of malignant behavior

Gene fusion analysis in renal cell carcinoma by FusionPlex RNA‐sequencing and correlations of molecular findings with clinicopathological features

Expression and Significance of Insulin Receptor Substrate 1 in Human Hepatocellular Carcinoma

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