Synergistic effects of PRIMA-1Met (APR-246) and Azacitidine in TP53-mutated myelodysplastic syndromes and acute myeloid leukemia.

Synergistic effects of PRIMA-1Met (APR-246) and Azacitidine in TP53-mutated myelodysplastic syndromes and acute myeloid leukemia. Haematologica. 2019 Sep 05;: Authors: Maslah N, Salomao N, Drevon L, Verger E, Partouche N, Ly P, Aubin P, Naoui N, Schlageter MH, Bally C, Miekoutima E, Rahmé R, Lehmann-Che J, Ades L, Fenaux P, Cassinat B, Giraudier S Abstract Myelodysplastic syndromes and acute myeloid leukemia with TP53 mutations are characterized by frequent relapses, poor or short responses, and poor survival with the currently available therapies including chemotherapy and 5-azacitidine. PRIMA-1Met (APR-246, APR) is a methylated derivative of PRIMA-1, which induces apoptosis in human tumor cells through restoration of the transcriptional transactivation function of mutant p53. We show here that low doses of APR on its own or in combination with 5-azacitidine reactivate the p53 pathway and induce an apoptosis program. Functionally, we demonstrate that APR exerts these activities on its own and that it synergizes with 5-azacitidine in TP53-mutated Myelodysplastic syndromes / acute myeloid leukemia cell lines and in TP53-mutated primary cells from Myelodysplastic syndromes / acute myeloid leukemia patients. Low doses of APR on its own or in combination with 5-azacitidine also show significant efficacy in vivo. Lastly, using transcriptomic analysis, we found that the APR + 5-azacitidine synergy was mediated by downregulation of the FLT...
Source: Haematologica - Category: Hematology Authors: Tags: Haematologica Source Type: research