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In vivo anti-tumor effect of PARP inhibition in IDH1/2 mutant MDS/AML resistant to targeted inhibitors of mutant IDH1/2

奥拉帕尼 IDH1 癌症研究 髓系白血病 异柠檬酸脱氢酶 IDH2型 净现值1 氯法拉滨 骨髓增生异常综合症 生物 合成致死 突变
作者
Rana Gbyli,Yuanbin Song,Wei Liu,Yimeng Gao,Giulia Biancon,Namrata S Chandhok,Xiaman Wang,Xiaoying Fu,Amisha Patel,Ranjini Sundaram,Toma Tebaldi,Padmavathi Mamillapalli,Amer M Zeidan,Richard A. Flavell,Thomas Prebet,Ranjit S Bindra,Stephanie Halene
出处
期刊:Leukemia [Springer Nature]
标识
DOI:10.1038/s41375-022-01536-x
摘要

Treatment options for patients with relapsed/refractory acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are scarce. Recurring mutations, such as mutations in isocitrate dehydrogenase-1 and -2 (IDH1/2) are found in subsets of AML and MDS, are therapeutically targeted by mutant enzyme-specific small molecule inhibitors (IDHmi). IDH mutations induce diverse metabolic and epigenetic changes that drive malignant transformation. IDHmi alone are not curative and resistance commonly develops, underscoring the importance of alternate therapeutic options. We were first to report that IDH1/2 mutations induce a homologous recombination (HR) defect, which confers sensitivity to poly (ADP)-ribose polymerase inhibitors (PARPi). Here, we show that the PARPi olaparib is effective against primary patient-derived IDH1/2-mutant AML/ MDS xeno-grafts (PDXs). Olaparib efficiently reduced overall engraftment and leukemia-initiating cell frequency as evident in serial transplantation assays in IDH1/2-mutant but not -wildtype AML/MDS PDXs. Importantly, we show that olaparib is effective in both IDHmi-naïve and -resistant AML PDXs, critical given the high relapse and refractoriness rates to IDHmi. Our pre-clinical studies provide a strong rationale for the translation of PARP inhibition to patients with IDH1/2-mutant AML/ MDS, providing an additional line of therapy for patients who do not respond to or relapse after targeted mutant IDH inhibition.
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