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

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...

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Published in:Leukemia 2022-05, Vol.36 (5), p.1313-1323
Main Authors: Gbyli, Rana, Song, Yuanbin, Liu, Wei, Gao, Yimeng, Biancon, Giulia, Chandhok, Namrata S, Wang, Xiaman, Fu, Xiaoying, Patel, Amisha, Sundaram, Ranjini, Tebaldi, Toma, Mamillapalli, Padmavathi, Zeidan, Amer M, Flavell, Richard A, Prebet, Thomas, Bindra, Ranjit S, Halene, Stephanie
Format: Article
Language:English
Subjects:
Acute myeloid leukemia
Anticancer properties
Enzyme Inhibitors - pharmacology
Epigenetics
Homologous recombination
Homology
Humans
Inhibitors
Isocitrate dehydrogenase
Isocitrate Dehydrogenase - genetics
Isocitrate Dehydrogenase - metabolism
Leukemia
Leukemia, Myeloid, Acute - drug therapy
Leukemia, Myeloid, Acute - genetics
Mutants
Mutation
Myelodysplastic syndrome
Myelodysplastic syndromes
Myelodysplastic Syndromes - drug therapy
Myelodysplastic Syndromes - genetics
Patients
Poly(ADP-ribose) polymerase
Poly(ADP-ribose) Polymerase Inhibitors - pharmacology
Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use
Recurrence
Ribose
Thermal resistance
Transplantation
Tumors
Xenografts
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Summary: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 (IDH i). IDH mutations induce diverse metabolic and epigenetic changes that drive malignant transformation. IDH i 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 IDH i-naïve and -resistant AML PDXs, critical given the high relapse and refractoriness rates to IDH i. 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.
ISSN:0887-6924
1476-5551
DOI:10.1038/s41375-022-01536-x