TGFβR–SMAD3 signaling induces resistance to PARP inhibitors Bac Viet Le1,2, Paulina Podszywalow-Bartnicka2, Silvia Maifrede1, Katherine Sullivan-Reed1, Margaret Nieborowska-Skorska1, Konstantin Golovine1, Juo-Chin Yao3, Reza Nejati4, Kathy Q. Cai4, Lisa Beatrice Caruso5, Julian Swatler2, Michal Dabrowski6, Zhaorui Lian7, Peter Valent8, Elisabeth M. Paietta9, Ross L. Levine10, Hugo F. Fernandez11, Martin S. Tallman10, Mark R. Litzow12, Jian Huang7, Grant A. Challen3, Daniel Link3, Italo Tempera5, Mariusz A. Wasik4, Katarzyna Piwocka2, Tomasz Skorski1 1 Sol Sherry Thrombosis Research Center and Fels Institute for Cancer Research and Molecular Biology, Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA 2 Nencki Institute of Experimental Biology, Polish Academy of Sciences, Laboratory of Cytometry, Warsaw, Poland 3 Division of Oncology, Department of Medicine, Washington University School of Medicine, Saint Louis, MO, USA 4 Department of Pathology, Fox Chase Cancer Center, Philadelphia, PA, USA 5 Fels Institute for Cancer Research & Molecular Biology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA. 6 Nencki Institute of Experimental Biology, Polish Academy of Sciences, Laboratory of Bioinformatics, Warsaw, Poland 7 Department of Pathology and Laboratory Medicine, Temple University Lewis Katz School of Medicine, Philadelphia, PA, USA 8 Medical University of Vienna and Ludwig-Boltzmann Institute for Hematology and Oncology, and Department of Internal Medicine I, Division of Hematology and Hemostaseology, Vienna, Austria 9 Albert Einstein College of Medicine-Montefiore Medical Center, Bronx, NY, USA 10 Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY. USA 11 Moffitt Malignant Hematology & Cellular Therapy at Memorial Healthcare System, Pembroke Pines, FL, USA 12 Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA Synthetic lethality triggered by PARP inhibitor (PARPi) yielded promising therapeutic results. Unfortunately, tumor cells acquire PARPi resistance, which is usually associated with restoration of homologous recombination, loss of PARP1 expression and/or loss of DNA double-strand break (DSB) end resection regulation. Here we identified a novel and constitutive mechanism of resistance to PARPi. We report that bone marrow microenvironment (BMM) facilitates DSB repair activity in leukemia cells to protect them against PARPi-mediated synthetic lethality. This effect depends on hypoxia-induced overexpression of transforming growth factor beta receptor (TGFbR) kinase on malignant cells, which is activated by bone marrow stromal cells - derived transforming growth factor beta 1 (TGF-b1). Genetic and/or pharmacological targeting of the TGF-b1 - TGFbR kinase axis resulted in restoration of sensitivity of malignant cells to PARPi in BMM and prolonged survival of leukemia-bearing mice. Our finding may lead to therapeutic application of TGFbR inhibitor in patients receiving PARP inhibitors.