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Maifrede S , Nieborowska-Skorska M , Sullivan K , Dasgupta Y , Podszywalow-Bartnicka P , Le BV , Solecka M , Lian Z , Belyaeva EA , Nersesyan A , Machnicki MM , Toma M , Chatain N , Rydzanicz M , Zhao H , Jelinek J , Piwocka K , Sliwinski T , Stoklosa T , Ploski R , Fischer T , Sykes SM , Koschmieder S , Bullinger L , Valent P , Wasik M , Huang J , Skorski T
Tyrosine kinase inhibitor-induced defects in DNA repair sensitize FLT3(ITD)-positive leukemia cells to PARP1 inhibitors
Blood. 2018 Jul 5;132(1) :67-77
PMID: 29784639    PMCID: PMC6034642    URL: https://www.ncbi.nlm.nih.gov/pubmed/29784639
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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.
Notes
1528-0020 Maifrede, Silvia Nieborowska-Skorska, Margaret Sullivan, Katherine Dasgupta, Yashodhara Podszywalow-Bartnicka, Paulina Le, Bac Viet Solecka, Martyna Lian, Zhaorui Belyaeva, Elizaveta A Nersesyan, Alina Machnicki, Marcin M Toma, Monika Chatain, Nicolas Rydzanicz, Malgorzata Zhao, Huaqing Jelinek, Jaroslav Piwocka, Katarzyna Sliwinski, Tomasz Stoklosa, Tomasz Ploski, Rafal Fischer, Thomas Sykes, Stephen M Koschmieder, Steffen Bullinger, Lars Valent, Peter Wasik, Mariusz Huang, Jian Skorski, Tomasz R01 CA134458/CA/NCI NIH HHS/United States R01 CA186238/CA/NCI NIH HHS/United States Journal Article United States Blood. 2018 May 21. pii: blood-2018-02-834895. doi: 10.1182/blood-2018-02-834895.