Open AccessIn vivo anti-tumor effect of PARP inhibition in IDH1/2 mutant MDS/AML resistant to targeted inhibitors of mutant IDH1/2
Author(s) -
Rana Gbyli,
Yuanbin Song,
Wei Liu,
Yimeng Gao,
Giulia Biancon,
Namrata Sonia Chandhok,
Xiaman Wang,
Xiaoying Fu,
Amisha Patel,
Ranjini K. Sundaram,
Toma Tebaldi,
Padmavathi Mamillapalli,
Amer M. Zeidan,
Richard A. Flavell,
Thomas Prébet,
Ranjit S. Bindra,
Stephanie Halene
Publication year - 2022
Publication title -
leukemia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.539
H-Index - 192
eISSN - 1476-5551
pISSN - 0887-6924
DOI - 10.1038/s41375-022-01536-x
Subject(s) - olaparib , idh1 , cancer research , myeloid leukemia , isocitrate dehydrogenase , npm1 , idh2 , biology , clofarabine , myelodysplastic syndromes , synthetic lethality , mutation , mutant , cytarabine , poly adp ribose polymerase , immunology , genetics , bone marrow , polymerase , gene , enzyme , biochemistry , chromosome , karyotype
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.