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

• Main Authors: 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
• Format: Article
• Language: English
• Published: Elsevier 2020-10-01
• Series: Cell Reports
• Subjects: PARP inhibitor resistance; TGFβR signaling; bone marrow microenvironment
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211124720312109
• ISSN: 2211-1247

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.