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Targeting FTO Suppresses Cancer Stem Cell Maintenance and Immune Evasion

Rui Su1, Lei Dong1, Yangchan Li2

  • 1Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA.

Cancer Cell
|June 13, 2020
PubMed

Insights

Fat mass and obesity-associated protein (FTO) inhibitors show potent anti-tumor effects. Targeting FTO suppresses cancer stem cell self-renewal and enhances immune response, offering new therapeutic strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • Fat mass and obesity-associated protein (FTO) is an RNA demethylase implicated in oncogenesis.
  • FTO's role in cancer presents a target for novel therapeutics.

Purpose of the Study:

  • To develop and evaluate small-molecule FTO inhibitors for cancer therapy.
  • To investigate the impact of FTO inhibition on cancer stem cell self-renewal and immune response.

Main Methods:

  • Development of two potent small-molecule FTO inhibitors.
  • Assessment of anti-tumor effects in various cancer types.
  • Genetic and pharmacological FTO inhibition in leukemia models.
  • Analysis of immune checkpoint gene expression and T cell cytotoxicity.

Main Results:

  • FTO inhibitors demonstrated significant anti-tumor activity across multiple cancer types.
  • FTO inhibition reduced leukemia stem/initiating cell self-renewal.
  • FTO suppression reprogrammed immune response by downregulating immune checkpoint genes, notably LILRB4.
  • FTO inhibition sensitized leukemia cells to T cell-mediated killing and overcame immune evasion.

Conclusions:

  • FTO plays a crucial role in cancer stem cell self-renewal and immune evasion.
  • Targeting FTO with small-molecule inhibitors offers a promising therapeutic strategy for various cancers, particularly leukemia.
  • FTO inhibition can enhance anti-cancer immunity and overcome treatment resistance.
Keywords:
FTOLILRB4LSC/LIC self-renewalN(6)-methyladenosine (m(6)A) modificationimmune checkpoint genesimmune evasioninhibitorsleukemiasolid tumorstherapeutics

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