TGFβR-SMAD3 signaling induces resistance to PARP inhibitors in the bone marrow microenvironment Journal Article
| Authors: | Le, B. V.; Podszywalow-Bartnicka, P.; Maifrede, S.; Sullivan-Reed, K.; Nieborowska-Skorska, M.; Golovine, K.; Yao, J. C.; Nejati, R.; Cai, K. Q.; Caruso, L. B.; Swatler, J.; Dabrowski, M.; Lian, Z.; Valent, P.; Paietta, E. M.; Levine, R. L.; Fernandez, H. F.; Tallman, M. S.; Litzow, M. R.; Huang, J.; Challen, G. A.; Link, D.; Tempera, I.; Wasik, M. A.; Piwocka, K.; Skorski, T. |
| Article Title: | TGFβR-SMAD3 signaling induces resistance to PARP inhibitors in the bone marrow microenvironment |
| Abstract: | Le et al. show that the TGF-β1-TGFβR kinase-SMAD3 pathway protects leukemia cells from PARP inhibitor (PARPi)-mediated synthetic lethality in the bone marrow microenvironment. The targeting of the TGF-β1 axis restored the sensitivity of leukemia cells to PARPi and prolonged survival of leukemia-bearing mice. © 2020 The Author(s) 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. © 2020 The Author(s) |
| Keywords: | bone marrow microenvironment; parp inhibitor resistance; tgfβr signaling |
| Journal Title: | Cell Reports |
| Volume: | 33 |
| Issue: | 1 |
| ISSN: | 2211-1247 |
| Publisher: | Cell Press |
| Date Published: | 2020-10-06 |
| Start Page: | 108221 |
| Language: | English |
| DOI: | 10.1016/j.celrep.2020.108221 |
| PUBMED: | 33027668 |
| PROVIDER: | scopus |
| PMCID: | PMC7578922 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 November 2020 -- Source: Scopus |
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