TGFβR-SMAD3 Signaling Induces Resistance to PARP Inhibitors in the Bone Marrow Microenvironment.
作者： Bac Viet Le , Paulina Podszywalow-Bartnicka , Silvia Maifrede , Katherine Sullivan-Reed , Margaret Nieborowska-Skorska
DOI: 10.1016/J.CELREP.2020.108221
关键词:
摘要: 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 PARP1 expression, and/or DNA double-strand break (DSB) end resection regulation. Here, we identify a constitutive mechanism resistance to PARPi. We report that bone marrow microenvironment (BMM) facilitates DSB repair activity in leukemia protect them against PARPi-mediated synthetic lethality. This effect depends on hypoxia-induced overexpression transforming growth factor beta receptor (TGFβR) kinase malignant cells, activated stromal cells-derived 1 (TGF-β1). Genetic pharmacological targeting TGF-β1-TGFβR axis results sensitivity BMM and prolongs survival leukemia-bearing mice. Our finding may lead application TGFβR patients receiving PARPis.
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