Research Papers:

Sorafenib inhibits therapeutic induction of necroptosis in acute leukemia cells

Friederike Feldmann, Barbara Schenk, Sofie Martens, Peter Vandenabeele and Simone Fulda _

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Oncotarget. 2017; 8:68208-68220. https://doi.org/10.18632/oncotarget.19919

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Friederike Feldmann1,2,3, Barbara Schenk1, Sofie Martens4,5, Peter Vandenabeele4,5 and Simone Fulda1,2,3

1Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt, Germany

2German Cancer Consortium (DKTK), Partner Site, Frankfurt, Germany

3German Cancer Research Center (DKFZ), Heidelberg, Germany

4Inflammation Research Center, VIB, Ghent, Belgium

5Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium

Correspondence to:

Simone Fulda, email: [email protected]

Keywords: necroptosis, cell death, Sorafenib, Smac, leukemia

Received: June 09, 2017     Accepted: July 25, 2017     Published: August 04, 2017


Induction of necroptosis has emerged as an alternative approach to trigger programmed cell death, in particular in apoptosis-resistant cancer cells. Recent evidence suggests that kinase inhibitors targeting oncogenic B-RAF can also affect Receptor-interacting serine/threonine-protein kinase (RIP)1 and RIP3. Sorafenib, a multi-targeting kinase inhibitor with activity against B-RAF, is used for the treatment of acute leukemia. In the present study, we therefore investigated whether Sorafenib interferes with therapeutic induction of necroptosis in acute leukemia. Here, we report that Sorafenib inhibits necroptotic signaling and cell death in two models of necroptosis in acute leukemia. Sorafenib significantly reduces Second mitochondria-derived activator of caspases (Smac) mimetic-induced necroptosis in apoptosis-resistant acute myeloid leukemia (AML) cells as well as Smac mimetic/Tumor Necrosis Factor (TNF)α-induced necroptosis in FADD-deficient acute lymphoblastic leukemia (ALL) cells. Sub- to low micromolar concentrations of Sorafenib corresponding to its plasma levels reported in cancer patients are sufficient to inhibit necroptosis, emphasizing the clinical relevance of our findings. Furthermore, Sorafenib blocks Smac mimetic-mediated phosphorylation of mixed-lineage kinase domain-like protein (MLKL) that marks its activation, indicating that Sorafenib targets components upstream of MLKL such as RIP1 and RIP3. Intriguingly, Sorafenib reduces the Smac mimetic/TNFα-stimulated interaction of RIP1 with RIP3 and MLKL, demonstrating that it interferes with the assembly of the necrosome complex. Importantly, Sorafenib significantly protects primary, patient-derived AML blasts from Smac mimetic-induced necroptosis. By demonstrating that Sorafenib limits the anti-leukemic activity of necroptosis-inducing drugs in acute leukemia cells, our study has important implications for the use of Sorafenib in the treatment of acute leukemia.

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