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NT157 exhibits antineoplastic effects by targeting IRS and STAT3/5 signaling in multiple myeloma

Gustavo Nery de Queiroz1, Keli Lima2, Livia Bassani Lins de Miranda1

  • 1Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.

Hematology, Transfusion and Cell Therapy
|March 24, 2024
PubMed

Insights

This study explores the IGF1/IGF1R pathway in multiple myeloma (MM), finding a novel inhibitor, NT157, effectively targets MM cells. NT157 shows promise for enhancing MM therapy by reducing cell viability and promoting apoptosis.

Area of Science:

  • Hematology
  • Oncology
  • Molecular Biology

Background:

  • Multiple myeloma (MM) is a recurring hematological malignancy lacking a definitive cure.
  • The Insulin-like Growth Factor 1 (IGF1)/IGF1 Receptor (IGF1R) axis plays a critical role in MM cell survival, proliferation, migration, and patient outcomes.
  • Current therapeutic strategies for MM require novel approaches to overcome resistance and recurrence.

Purpose of the Study:

  • To investigate the role of the IGF1/IGF1R signaling axis in multiple myeloma.
  • To evaluate the efficacy of a novel inhibitor, NT157, targeting the IGF1/IGF1R pathway in MM.
  • To elucidate the molecular mechanisms underlying NT157's anti-cancer effects in MM.

Main Methods:

  • Comparative analysis of IGF1R signaling-related gene expression in MM patients and healthy donors.
  • Assessment of IGF1R-related protein expression in MM cell lines.
  • Gene dependence analysis to identify key signaling components.
  • In vitro evaluation of NT157's effects on MM cell viability, proliferation, cell cycle, and apoptosis.
  • Analysis of NT157's impact on key intracellular signaling molecules (IRS, STATs, RPS6) and oncogenes/tumor suppressors.

Main Results:

  • Significant distinctions in IGF1R signaling gene expression were observed between MM patients and healthy donors.
  • MM cell lines exhibited varied expression patterns of IGF1R-related proteins.
  • NT157 demonstrated significant inhibitory effects on MM cell viability, clonal growth, cell cycle progression, and survival.
  • NT157 reduced IRS2 expression and inhibited STAT3, STAT5, and RPS6 activation.
  • NT157 modulated oncogenes and tumor suppressors, promoting a tumor-suppressive molecular profile.

Conclusions:

  • The IGF1/IGF1R/IRS signaling axis is differentially activated in multiple myeloma cells.
  • NT157 effectively targets crucial molecular players within the IGF1/IGF1R/IRS pathway in MM.
  • NT157 exhibits potent antiproliferative and pro-apoptotic effects in MM cells, suggesting its potential as a novel therapeutic agent for MM.
Keywords:
Hematological malignancyIGF1/IGF1R axisMultiple myelomaNT157Tumor suppression

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