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

• Published in: Leukemia Vol. 36; no. 5; pp. 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: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2022; Nature Publishing Group
• Subjects: 13/100; 13/106; 13/109; 13/21; 13/31; 13/51; 45; 45/23; 64; 64/60; 692/699/1541/1990/1673; 692/699/1541/1990/283/1897; Acute myeloid leukemia; Anticancer properties; Cancer Research; Critical Care Medicine; Enzyme Inhibitors - pharmacology; Epigenetics; Hematology; Homologous recombination; Homology; Humans; Inhibitors; Intensive; Internal Medicine; Isocitrate dehydrogenase; Isocitrate Dehydrogenase - genetics; Isocitrate Dehydrogenase - metabolism; Leukemia; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - genetics; Medicine; Medicine & Public Health; Mutants; Mutation; Myelodysplastic syndrome; Myelodysplastic syndromes; Myelodysplastic Syndromes - drug therapy; Myelodysplastic Syndromes - genetics; Oncology; 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
• ISSN: 0887-6924; 1476-5551; 1476-5551
• DOI: 10.1038/s41375-022-01536-x

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 m i). IDH mutations induce diverse metabolic and epigenetic changes that drive malignant transformation. IDH m 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 m i-naïve and -resistant AML PDXs, critical given the high relapse and refractoriness rates to IDH m 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.