mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt

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Updated: Aug 13, 2026

Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants
07:38

Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants

Published on: June 6, 2025

Kathryn E O'Reilly1, Fredi Rojo, Qing-Bai She

  • 1Program in Molecular Pharmacy and Chemistry, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.

Cancer Research
|February 3, 2006
PubMed

Insights

mTOR inhibitors show limited antitumor activity because they increase insulin receptor substrate-1, reactivating Akt. Combining mTOR inhibition with IGF-I receptor blockade may improve cancer therapy by preventing this feedback loop.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • The phosphoinositide-3-kinase/Akt/mammalian target of rapamycin (mTOR) pathway is crucial for cell growth and survival.
  • Mutational activation of this pathway is common in various cancers.
  • mTOR inhibitors like rapamycin show promise in preclinical models but have modest clinical antitumor activity.

Purpose of the Study:

  • To investigate the mechanisms underlying the limited efficacy of mTOR inhibitors in cancer patients.
  • To explore strategies for enhancing the antitumor activity of mTOR inhibitors.

Main Methods:

  • Utilized cancer cell lines and patient tumors treated with RAD001 (a rapamycin derivative).
  • Assessed the expression of insulin receptor substrate-1 and Akt activation.
  • Investigated the role of insulin-like growth factor I (IGF-I) receptor signaling in response to mTOR inhibition.

Main Results:

  • mTOR inhibition by RAD001 led to increased insulin receptor substrate-1 expression, abrogating feedback inhibition and causing Akt activation.
  • IGF-I receptor inhibition prevented rapamycin-induced Akt activation and sensitized tumor cells to mTOR inhibition.
  • IGF-I reversed the antiproliferative effects of rapamycin.

Conclusions:

  • Feedback down-regulation of receptor tyrosine kinase signaling is a common event in tumors with constitutive mTOR activation.
  • Reversal of this feedback loop by rapamycin may limit its therapeutic effects.
  • Combination therapy targeting both mTOR and preventing Akt activation (e.g., via IGF-I receptor inhibition) may offer improved antitumor activity.

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