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| Blood. 2018 May 21. pii: blood-2018-02-834895. doi: 10.1182/blood-2018-02-834895 |
| Tyrosine kinase inhibitor-induced defects in DNA repair sensitize FLT3(ITD)-positive leukemia cells to PARP1 inhibitors. |
| Maifrede S1, Nieborowska-Skorska M2, Sullivan K3, Dasgupta Y4, Podszywalow-Bartnicka P5, Le BV6, Solecka M7, Lian Z8, Belyaeva EA9, Nersesyan A10, Machnicki MM11, Toma M12, Chatain N13, Rydzanicz M14, Zhao H15, Jelinek J16, Piwocka K17, Sliwinski T18, Stoklosa T19, Ploski R20, Fischer T21, Sykes SM22, Koschmieder S23, Bullinger L24, Valent P25, Wasik M26, Huang J27, Skorski T28 |
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Abstract Mutations in the FMS-like tyrosine-kinase 3 (FLT3) such as internal tandem duplications (ITD) can be found in up to 23% of patients with acute myeloid leukemia (AML) and confer a poor prognosis. Current treatment options for FLT3(ITD)-positive AMLs include genotoxic therapy and FLT3 inhibitors (FLT3i), which are rarely curative. PARP1 inhibitors (PARP1i) have been successfully applied to induce synthetic lethality in tumors harboring BRCA1/2 mutations and displaying homologous recombination (HR) deficiency. We show here that inhibition of FLT3(ITD) kinase by the FLT3 kinase inhibitor (FLT3i) AC220 caused downregulation of DNA repair proteins BRCA1, BRCA2, PALB2, RAD51, and LIG4, resulting in inhibition of two major DNA double-strand breaks (DSBs) repair pathways, HR and non-homologous end-joining (NHEJ). PARP1i, olaparib and BMN673, caused accumulation of lethal DSBs and cell death in AC220-treated FLT3(ITD)-positive leukemia cells thus mimicking synthetic lethality. Moreover, the combination of FLT3i and PARP1i eliminated FLT3(ITD)-positive quiescent and proliferating leukemia stem cells as well as leukemic progenitors from human and mouse leukemia samples. Notably, the combination of AC220 and BMN673 significantly delayed disease onset and effectively reduced leukemia initiating cells in a FLT3(ITD)-positive primary AML xenograft mouse model. In conclusion, we postulate that FLT3i-induced deficiencies in DSB repair pathways sensitize FLT3(ITD)-positive AML cells to synthetic lethality triggered by PARP1i. Therefore FLT3(ITD) could be used as a precision medicine marker for identifying AML patients that may benefit from a therapeutic regimen combining FLT3 and PARP1 inhibitors. |
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Copyright © 2018 American Society of Hematology. |
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Publikations ID: 29784639 Quelle: öffnen |
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