Cell Reports (Oct 2020)
TGFβR-SMAD3 Signaling Induces Resistance to PARP Inhibitors in the Bone Marrow Microenvironment
- Bac Viet Le,
- Paulina Podszywalow-Bartnicka,
- Silvia Maifrede,
- Katherine Sullivan-Reed,
- Margaret Nieborowska-Skorska,
- Konstantin Golovine,
- Juo-Chin Yao,
- Reza Nejati,
- Kathy Q. Cai,
- Lisa Beatrice Caruso,
- Julian Swatler,
- Michal Dabrowski,
- Zhaorui Lian,
- Peter Valent,
- Elisabeth M. Paietta,
- Ross L. Levine,
- Hugo F. Fernandez,
- Martin S. Tallman,
- Mark R. Litzow,
- Jian Huang,
- Grant A. Challen,
- Daniel Link,
- Italo Tempera,
- Mariusz A. Wasik,
- Katarzyna Piwocka,
- Tomasz Skorski
Affiliations
- Bac Viet Le
- Sol 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
- Paulina Podszywalow-Bartnicka
- Nencki Institute of Experimental Biology, Polish Academy of Sciences, Laboratory of Cytometry, Warsaw, Poland
- Silvia Maifrede
- Sol Sherry Thrombosis Research Center and Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
- Katherine Sullivan-Reed
- Sol Sherry Thrombosis Research Center and Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
- Margaret Nieborowska-Skorska
- Sol Sherry Thrombosis Research Center and Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
- Konstantin Golovine
- Sol Sherry Thrombosis Research Center and Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
- Juo-Chin Yao
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
- Reza Nejati
- Department of Pathology, Fox Chase Cancer Center, Philadelphia, PA, USA
- Kathy Q. Cai
- Department of Pathology, Fox Chase Cancer Center, Philadelphia, PA, USA
- Lisa Beatrice Caruso
- Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
- Julian Swatler
- Nencki Institute of Experimental Biology, Polish Academy of Sciences, Laboratory of Cytometry, Warsaw, Poland
- Michal Dabrowski
- Nencki Institute of Experimental Biology, Polish Academy of Sciences, Laboratory of Bioinformatics, Warsaw, Poland
- Zhaorui Lian
- Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
- Peter Valent
- Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna and Ludwig-Boltzmann Institute for Hematology and Oncology, Vienna, Austria
- Elisabeth M. Paietta
- Albert Einstein College of Medicine-Montefiore Medical Center, Bronx, NY, USA
- Ross L. Levine
- Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Hugo F. Fernandez
- Moffitt Malignant Hematology & Cellular Therapy at Memorial Healthcare System, Pembroke Pines, FL, USA
- Martin S. Tallman
- Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Mark R. Litzow
- Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA
- Jian Huang
- Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
- Grant A. Challen
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
- Daniel Link
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
- Italo Tempera
- Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
- Mariusz A. Wasik
- Department of Pathology, Fox Chase Cancer Center, Philadelphia, PA, USA
- Katarzyna Piwocka
- Nencki Institute of Experimental Biology, Polish Academy of Sciences, Laboratory of Cytometry, Warsaw, Poland; Corresponding author
- Tomasz Skorski
- Sol Sherry Thrombosis Research Center and Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA; Corresponding author
- Journal volume & issue
-
Vol. 33,
no. 1
p. 108221
Abstract
Summary: Synthetic lethality triggered by PARP inhibitor (PARPi) yields promising therapeutic results. Unfortunately, tumor cells acquire PARPi resistance, which is usually associated with the restoration of homologous recombination, loss of PARP1 expression, and/or loss of DNA double-strand break (DSB) end resection regulation. Here, we identify a constitutive mechanism of resistance to PARPi. We report that the bone marrow microenvironment (BMM) facilitates DSB repair activity in leukemia cells to protect them against PARPi-mediated synthetic lethality. This effect depends on the hypoxia-induced overexpression of transforming growth factor beta receptor (TGFβR) kinase on malignant cells, which is activated by bone marrow stromal cells-derived transforming growth factor beta 1 (TGF-β1). Genetic and/or pharmacological targeting of the TGF-β1-TGFβR kinase axis results in the restoration of the sensitivity of malignant cells to PARPi in BMM and prolongs the survival of leukemia-bearing mice. Our finding may lead to the therapeutic application of the TGFβR inhibitor in patients receiving PARPis.
