Synergistic effects of PRIMA-1^Met (APR-246) and 5-azacitidine in TP53-mutated myelodysplastic syndromes and acute myeloid leukemia

Abstract

M yelodysplastic 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 (AZA). PRIMA-1 Met (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. Here we show that low doses of APR on its own or in combination with AZA 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 AZA in TP53-mutated myelodysplastic syndromes (MDS) / acute myeloid leukemia (AML) cell lines and in TP53mutated primary cells from MDS / AML patients. Low doses of APR on its own or in combination with AZA also show significant efficacy in vivo. Lastly, using transcriptomic analysis, we found that the APR + AZA synergy was mediated by downregulation of the FLT3 pathway in drug-treated cells. Activation of the FLT3 pathway by FLT3 ligand reversed the inhibition of cell proliferation by APR + AZA. These data suggest that TP53-mutated MDS / AML may be better targeted by the addition of APR-246 to conventional treatments.

Functional Classification of TP53 Mutations in Acute Myeloid Leukemia

“…APR-246 is a small molecule designed to shift mutant p53 towards a wild type confirmation, thus inducing apoptosis of neoplastic cells [50][51][52]. Synergistic effects of this drug and azacitidine have been demonstrated in vitro using cells from patients with TP53-mutated AML and myelodysplastic syndromes (MDS) [53]. In a multiphase 1b/2 trial, APR-246 was given in combination with azacitidine to patients with TP53-mutated MDS and oligoblastic AML with preliminary results showing encouraging response rates of 85% [54].…”

Discordant Response of Systemic Mastocytosis Associated With Myelodysplastic Syndrome After Midostaurin and Allogeneic Hematopoietic Stem‐cell Transplantation

“… 17 APR-246 reactivates p53 protein function by restoring mutant p53 conformation, thereby inducing programed cell death in cancer cells. 18 …”

Targeting p53 in chronic lymphocytic leukemia

“…APR-246, alone or in combination with other drugs, has shown antitumor activity in different solid and hematological tumors. In myelodysplastic syndromes (MDS), APR-246 has demonstrated high efficacy especially in combination with azacytidine (AZA) [76]. Based on these promising results, a phase III international trial comparing AZA alone and AZA + APR 246 is ongoing in TP53 mutated MDS (NCT03745716).…”