Correlation between immunohistochemistry and RICTOR fluorescence in situ hybridization amplification in small cell lung carcinoma

Krencz, Ildikó; Sebestyén, Anna; Pápay, Judit; Lou, Yanyan; Lutz, Gabrielle F.; Majewicz, Tracy L.; Khoór, András

doi:10.1016/j.humpath.2019.08.018

Cited by 12 publications

(27 citation statements)

References 30 publications

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“…Assessment of mTORC2 activity was based on the co-expression of pmTOR and Rictor. Rictor immunopositivity without pmTOR and pS6 positivity was considered as the potential activation of the mTORC2 complex [ 23 , 24 ].…”

Section: Resultsmentioning

confidence: 99%

“…FISH was performed on 4-μm thick sections of FFPE tissue samples, as has been previously described [ 24 ]. After deparaffinization and pretreatment, samples were digested at 38 °C for 25 min (Vysis IntelliFISH Pretreatment saline sodium citrate solution and IntelliFISH Protease; Abbott Molecular, Abbott Park, IL, USA).…”

Section: Methodsmentioning

confidence: 99%

“…After post-hybridization washing and air drying, nuclei were counterstained with 4,6-diamino-2-fenilindol (DAPI I, Abbott Molecular). [ 24 ] Representative areas were selected based on hematoxylin and eosin slides and were evaluated counting 30 nuclei in at least two different areas of the tumor using a fluorescence microscope. The mean number of the signals per nucleus and the RICTOR /Chr5 ratio were determined; RICTOR copy number of less than 4 and a RICTOR /Chr5 ratio of less than 2 were considered negative, whereas RICTOR copy number of 6 or more and a RICTOR /Chr5 ratio of 2 or more were considered positive.…”

Section: Methodsmentioning

confidence: 99%

“…The mean number of the signals per nucleus and the RICTOR /Chr5 ratio were determined; RICTOR copy number of less than 4 and a RICTOR /Chr5 ratio of less than 2 were considered negative, whereas RICTOR copy number of 6 or more and a RICTOR /Chr5 ratio of 2 or more were considered positive. Cases with a RICTOR copy number between 4 and 6 and a RICTOR /Chr5 ratio of less than 2 were considered equivocal [ 24 ].…”

Section: Methodsmentioning

confidence: 99%

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Characterization of mTOR Activity and Metabolic Profile in Pediatric Rhabdomyosarcoma

Felkai

Krencz

Kiss

et al. 2020

Cancers

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mTOR activation has been observed in rhabdomyosarcoma (RMS); however, mTOR complex (mTORC) 1 inhibition has had limited success thus far. mTOR activation alters the metabolic pathways, which is linked to survival and metastasis. These pathways have not been thoroughly analyzed in RMSs. We performed immunohistochemistry on 65 samples to analyze the expression of mTOR complexes (pmTOR, pS6, Rictor), and several metabolic enzymes (phosphofructokinase, lactate dehydrogenase-A, β-F1-ATPase, glucose-6-phosphate dehydrogenase, glutaminase). RICTOR amplification, as a potential mechanism of Rictor overexpression, was analyzed by FISH and digital droplet PCR. In total, 64% of the studied primary samples showed mTOR activity with an mTORC2 dominance (82%). Chemotherapy did not cause any relevant change in mTOR activity. Elevated mTOR activity was associated with a worse prognosis in relapsed cases. RICTOR amplification was not confirmed in any of the cases. Our findings suggest the importance of the Warburg effect and the pentose-phosphate pathway beside a glutamine demand in RMS cells. The expression pattern of the studied mTOR markers can explain the inefficacy of mTORC1 inhibitor therapy. Therefore, we suggest performing a detailed investigation of the mTOR profile before administering mTORC1 inhibitor therapy. Furthermore, our findings highlight that targeting the metabolic plasticity could be an alternative therapeutic approach.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Characterization of mTOR Activity and Metabolic Profile in Pediatric Rhabdomyosarcoma

Felkai

Krencz

Kiss

et al. 2020

Cancers

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“…Based on a comprehensive genomic analysis, genetic alterations of the PI3K/Akt/mTOR pathway (including PIK3CA , PTEN , AKT2 , AKT3 , RICTOR , and MTOR genes) are present in 36% of the SCLC patients [ 30 ]. Among these genes, RICTOR amplification, coding for the scaffold protein of mTORC2, has been observed as the most common targetable genetic alteration in SCLC with a frequency of 6 to 15% in different studies (Table 1 ) [ 31 – 33 ]. The expression of mTOR pathway activation markers has also been studied by immunohistochemistry, and it has been described that the expression of p-mTOR, a marker for mTOR kinase activity, is present in more than half (55 to 87.8%) of the cases [ 34 , 35 ].…”

Section: Mtor Pathway Alterations In Small Cell Lung Carcinomasmentioning

confidence: 99%

Progression and metastasis of small cell lung carcinoma: the role of the PI3K/Akt/mTOR pathway and metabolic alterations

Krencz

Sztankovics

Dankó

et al. 2021

Cancer Metastasis Rev

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Small cell lung carcinoma (SCLC) is characterized by high metastatic rate and poor prognosis. The platinum-based chemotherapy still represents the backbone of the therapy; however, acquired resistance develops almost in all patients. Although SCLC has been formerly considered a homogeneous disease, recent advances in SCLC research have highlighted the importance of inter- and intratumoral heterogeneity and have resulted in the subclassification of SCLC. The newly described SCLC subtypes are characterized by distinct biological behavior and vulnerabilities that can be therapeutically exploited. The PI3K/Akt/mTOR pathway is frequently affected in SCLC, and its activation represents a promising therapeutic target. Since the mTOR pathway is a master regulator of cellular metabolism, its alterations may also influence the bioenergetic processes of SCLC cells. Despite the encouraging preclinical results, both mTOR and metabolic inhibitors have met limited clinical success so far. Patient selection for personalized therapy, the development of rational drug combinations, and a better understanding of heterogeneity and spatiotemporal evolution of the tumor cells may improve efficacy and can help to overcome acquired resistance. Here we provide a summary of current investigations regarding the role of the mTOR pathway and metabolic alterations in the progression and metastasis formation of SCLC.

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mTOR in Lung Neoplasms

Krencz

Sebestyén

Khoór

2020

Pathol. Oncol. Res.

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Correlation between immunohistochemistry and RICTOR fluorescence in situ hybridization amplification in small cell lung carcinoma

Cited by 12 publications

References 30 publications

Characterization of mTOR Activity and Metabolic Profile in Pediatric Rhabdomyosarcoma

Characterization of mTOR Activity and Metabolic Profile in Pediatric Rhabdomyosarcoma

Progression and metastasis of small cell lung carcinoma: the role of the PI3K/Akt/mTOR pathway and metabolic alterations

mTOR in Lung Neoplasms

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