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TGFβR-SMAD3 Signaling Induces Resistance to PARP Inhibitors in the Bone Marrow Microenvironment

Bac Viet Le1, Paulina Podszywalow-Bartnicka2, Silvia Maifrede3

  • 1Sol Sherry Thrombosis Research Center and Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA; Nencki Institute of Experimental Biology, Polish Academy of Sciences, Laboratory of Cytometry, Warsaw, Poland.

Cell Reports
|October 7, 2020
PubMed

Insights

The bone marrow microenvironment protects leukemia cells from PARP inhibitor therapy by enhancing DNA repair. Targeting the TGF-β1-TGFβR pathway restores PARPi sensitivity, improving survival in leukemia models.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Poly (ADP-ribose) polymerase inhibitors (PARPi) show promise in cancer therapy by exploiting synthetic lethality.
  • Tumor cells develop resistance to PARPi through mechanisms like homologous recombination restoration or loss of DNA repair regulation.
  • Understanding novel resistance mechanisms is crucial for improving PARPi efficacy.

Purpose of the Study:

  • To identify a constitutive mechanism of PARPi resistance in leukemia.
  • To investigate the role of the bone marrow microenvironment (BMM) in mediating PARPi resistance.
  • To evaluate the therapeutic potential of targeting the identified resistance pathway.

Main Methods:

  • Investigated the interaction between leukemia cells and the BMM.
  • Assessed DNA double-strand break (DSB) repair activity in leukemia cells within the BMM.
  • Utilized genetic and pharmacological approaches to target the transforming growth factor beta receptor (TGFβR) kinase pathway.
  • Evaluated the effect of targeting this pathway on PARPi sensitivity and mouse survival.

Main Results:

  • The BMM protects leukemia cells against PARPi-mediated synthetic lethality by facilitating DSB repair.
  • This protective effect is mediated by hypoxia-induced overexpression of TGFβR kinase on malignant cells, activated by bone marrow stromal cell-derived TGF-β1.
  • Targeting the TGF-β1-TGFβR kinase axis restored sensitivity to PARPi in leukemia cells within the BMM.
  • Inhibition of this axis prolonged the survival of leukemia-bearing mice.

Conclusions:

  • The bone marrow microenvironment confers resistance to PARP inhibitors in leukemia via the TGF-β1-TGFβR pathway.
  • Targeting the TGF-β1-TGFβR axis can overcome PARPi resistance and enhance therapeutic outcomes in leukemia.
  • TGFβR inhibitors represent a potential therapeutic strategy for patients receiving PARPi treatment.
Keywords:
PARP inhibitor resistanceTGFβR signalingbone marrow microenvironment

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