Related Experiment Video

Updated: May 8, 2026

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
08:49

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries

Published on: January 22, 2019

An isogenic cell panel identifies compounds that inhibit proliferation of mTOR-pathway addicted cells by different

Lorenza Wyder Peters1, Klaus D Molle, Anke Thiemeyer

  • 11Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.

Journal of Biomolecular Screening
|August 20, 2013
PubMed

Insights

Researchers screened for compounds targeting cancer cells dependent on the mTOR pathway. They identified two novel compound classes that inhibit cell proliferation through distinct mechanisms, offering new therapeutic avenues.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • The mechanistic target of rapamycin (mTOR) pathway integrates nutrient and growth factor signals, promoting cell growth and proliferation.
  • Dysregulation of the mTOR pathway, particularly in tumors with PTEN mutations, leads to uncontrolled cell growth.
  • Targeting the mTOR pathway is a key strategy in cancer therapy.

Purpose of the Study:

  • To identify novel compounds that selectively inhibit the proliferation of cancer cells addicted to the PTEN/mTOR pathway.
  • To characterize the mechanisms of action of these identified compounds.

Main Methods:

  • High-throughput screening using an isogenic cell line system with specific PTEN/mTOR pathway mutations.
  • Characterization of compound mechanisms, including target engagement and downstream effects.
  • Assessment of effects on signaling components like S6 ribosomal protein phosphorylation and cyclin D3 levels.

Main Results:

  • Two distinct classes of compounds were identified.
  • Class 1 compounds inhibit PTEN/mTOR signaling, reducing S6 ribosomal protein phosphorylation and cyclin D3, without being ATP-competitive or FKBP12-dependent.
  • Class 2 compounds act as farnesylation inhibitors, impacting GTPase activity and inducing oxidative stress.

Conclusions:

  • An isogenic cell system is effective for discovering compounds targeting pathway-addicted cancer cells.
  • The identified compounds exhibit novel mechanisms of action, distinct from existing therapies like rapamycin.
  • These findings provide new therapeutic strategies for cancers with PTEN/mTOR pathway dysregulation.
Keywords:
farnesylationisogenic cell linesmTORoncogene addictionsynthetic lethality

More Related Videos

A Strategy to Identify Compounds that Affect Cell Growth and Survival in Cultured Mammalian Cells at Low-to-Moderate Throughput12:22

A Strategy to Identify Compounds that Affect Cell Growth and Survival in Cultured Mammalian Cells at Low-to-Moderate Throughput

Published on: September 22, 2019

Potentiation of Anticancer Antibody Efficacy by Antineoplastic Drugs: Detection of Antibody-drug Synergism Using the Combination Index Equation15:04

Potentiation of Anticancer Antibody Efficacy by Antineoplastic Drugs: Detection of Antibody-drug Synergism Using the Combination Index Equation

Published on: January 19, 2019

Related Concept Videos

mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a rapamycin-insensitive companion...
Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
Targeted Cancer Therapies02:57

Targeted Cancer Therapies

The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against specific...