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.

PubMed

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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