mTOR hyperactivity and RICTOR amplification as targets for personalized treatments in malignancies
Dániel Sztankovics1, Dorottya Moldvai1, Gábor Petővári1
1Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.
Abstract:
The increasing knowledge of molecular alterations in malignancies, including mutations and regulatory failures in the mTOR (mechanistic target of rapamycin) signaling pathway, highlights the importance of mTOR hyperactivity as a validated target in common and rare malignancies. This review summarises recent findings on the characterization and prognostic role of mTOR kinase complexes (mTORC1 and mTORC2) activity regarding differences in their function, structure, regulatory mechanisms, and inhibitor sensitivity. We have recently identified new tumor types with RICTOR (rapamycin-insensitive companion of mTOR) amplification and associated mTORC2 hyperactivity as useful potential targets for developing targeted therapies in lung cancer and other newly described malignancies. The activity of mTOR complexes is recommended to be assessed and considered in cancers before mTOR inhibitor therapy, as current first-generation mTOR inhibitors (rapamycin and analogs) can be ineffective in the presence of mTORC2 hyperactivity. We have introduced and proposed a marker panel to determine tissue characteristics of mTOR activity in biopsy specimens, patient materials, and cell lines. Ongoing phase trials of new inhibitors and combination therapies are promising in advanced-stage patients selected by genetic alterations, molecular markers, and/or protein expression changes in the mTOR signaling pathway. Hopefully, the summarized results, our findings, and the suggested characterization of mTOR activity will support therapeutic decisions.
Insights
Hyperactivity in the mechanistic target of rapamycin (mTOR) pathway is a key cancer target. Assessing mTORC1/mTORC2 activity is crucial for effective mTOR inhibitor therapy, especially with new targeted treatments emerging.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- The mechanistic target of rapamycin (mTOR) signaling pathway is frequently dysregulated in various cancers.
- Understanding the distinct roles and regulation of mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) is critical for cancer therapy.
Purpose of the Study:
- To review recent findings on mTORC1 and mTORC2 characterization, prognostic significance, and inhibitor sensitivity.
- To highlight novel tumor types with RICTOR amplification and mTORC2 hyperactivity as therapeutic targets.
- To propose methods for assessing mTOR activity to guide treatment decisions.
Main Methods:
- Literature review of recent findings on mTOR signaling in malignancies.
- Identification of new tumor types with RICTOR amplification and mTORC2 hyperactivity.
- Proposal of a marker panel for assessing mTOR activity in clinical samples.
Main Results:
- mTORC1 and mTORC2 exhibit distinct functions, structures, regulatory mechanisms, and inhibitor sensitivities.
- RICTOR amplification leading to mTORC2 hyperactivity is identified in new malignancies, including lung cancer.
- Current mTOR inhibitors may be ineffective against mTORC2 hyperactivity, necessitating activity assessment.
Conclusions:
- Assessing mTOR complex activity is recommended before initiating mTOR inhibitor therapy.
- Novel targeted therapies and combination treatments targeting specific mTOR alterations show promise for advanced-stage cancers.
- The proposed marker panel can aid in characterizing mTOR activity and supporting therapeutic decisions.
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