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Le BV , Podszywalow-Bartnicka P , Maifrede S , Sullivan-Reed K , Nieborowska-Skorska M , Golovine K , Yao JC , Nejati R , Cai KQ , Caruso LB , Swatler J , Dabrowski M , Lian Z , Valent P , Paietta EM , Levine RL , Fernandez HF , Tallman MS , Litzow MR , Huang J , Challen GA , Link D , Tempera I , Wasik MA , Piwocka K , Skorski T
TGFβR-SMAD3 Signaling Induces Resistance to PARP Inhibitors in the Bone Marrow Microenvironment
Cell Rep. 2020 Oct 6;33(1) :108221
PMID: 33027668    PMCID: PMC7578922   
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Abstract
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.
Notes
2211-1247 Le, Bac Viet Podszywalow-Bartnicka, Paulina Maifrede, Silvia Sullivan-Reed, Katherine Nieborowska-Skorska, Margaret Golovine, Konstantin Yao, Juo-Chin Nejati, Reza Cai, Kathy Q Caruso, Lisa Beatrice Swatler, Julian Dabrowski, Michal Lian, Zhaorui Valent, Peter Paietta, Elisabeth M Levine, Ross L Fernandez, Hugo F Tallman, Martin S Litzow, Mark R Huang, Jian Challen, Grant A Link, Daniel Tempera, Italo Wasik, Mariusz A Piwocka, Katarzyna Skorski, Tomasz R01 CA186238/CA/NCI NIH HHS/United States R01 CA244044/CA/NCI NIH HHS/United States R01 CA247707/CA/NCI NIH HHS/United States Journal Article Cell Rep. 2020 Oct 6;33(1):108221. doi: 10.1016/j.celrep.2020.108221.