Characterization of mTOR Activity and Metabolic Profile in Pediatric Rhabdomyosarcoma
Open accessAbstract
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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mTOR inhibitors could inhibit tumor progression as having a complex modifying role on metabolism.
“mTOR inhibitors could inhibit tumor progression as having a complex modifying role on metabolism [108–113].”
From Hypoxia Signaling in Cancer: From Basics to Clinical Practice (2021) · cites this paper as [108]
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- Authors
- Felkai, L., Krencz, I., Kiss, D. J., Nagy, N., Petővári, G., Dankó, T., Micsík, T., Khoor, A., Tornóczky, T., Sápi, Z., Sebestyén, A., & Csóka, M.
- Affiliations
- Semmelweis University (HU)
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Jacksonville, FL 32224, USA
- University of Pecs (HU)
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, 1085 Budapest, Hungary
- Corresponding author
- Sebestyén, Anna
- Csóka, Monika
- ORCID
- Venue
- Cancers
- Publisher
- MDPI AG
- Published
- 2020-07-17
- Volume
- 12
- Issue
- 7
- Pages
- 1947
- ISSN
- 2072-6694 (ISSN-L)
- PMC
- PMC7409076
- OpenAlex
- W3043789017
- Cited by
- 13
- References
- 51
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 2 · 2023: 2 · 2022: 2 · 2021: 4
- FWCI
- 0.65
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cancers (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Hungarian Pediatric Oncology Network (10/MGYH-MGYGYT/2018, MGYGYT/2019)
- National Research, Development and Innovation Office (NKFI-FK-128404)
- New National Excellence Program of the Ministry of Human Capacities (ÚNKP-19-3-1/3.)
- Hungarian National Research, Development and Innovation Office (NVKP_16-1-2016-0004)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Sarcoma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- rhabdomyosarcoma, childhood cancer, mTOR signaling, mTORC1 inhibition, mTORC2, Warburg effect, pentose phosphate pathway, glutamine metabolism, cancer metabolism, metabolic plasticity, prognosis, relapse, chemotherapy response
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