The oral HDAC inhibitor pracinostat (SB939) is efficacious and synergistic with the JAK2 inhibitor pacritinib (SB1518) in preclinical models of AML

TLDR

Acute myeloid leukemia is treated with aggressive chemotherapy that is poorly tolerated in many elderly patients, and although FLT3, JAK2, and HDAC inhibitors have been tested clinically, they have shown only modest single‑agent activity, underscoring the need for more effective, less toxic therapies. Pracinostat and the JAK2/FLT3 inhibitor pacritinib jointly block JAK‑STAT signaling in AML cells harboring JAK2(V617F) mutations and also suppress FLT3 signaling, producing synergistic effects in vitro and in two AML mouse models. The combination of pracinostat and pacritinib markedly reduced AML cell proliferation, induced apoptosis, and in vivo synergistically inhibited tumor growth, metastasis, and JAK2/FLT signaling while normalizing tumor‑associated cytokines, demonstrating potent anti‑AML efficacy.

Abstract

Acute myeloid leukemia (AML) is currently treated with aggressive chemotherapy that is not well tolerated in many elderly patients, hence the unmet medical need for effective therapies with less toxicity and better tolerability. Inhibitors of FMS-like tyrosine kinase 3 (FLT3), JAK2 and histone deacetylase inhibitors (HDACi) have been tested in clinical studies, but showed only moderate single-agent activity. High efficacy of the HDACi pracinostat treating AML and synergy with the JAK2/FLT3 inhibitor pacritinib is demonstrated. Both compounds inhibit JAK-signal transducer and activator of transcription (STAT) signaling in AML cells with JAK2(V617F) mutations, but also diminish FLT3 signaling, particularly in FLT3-ITD (internal tandem duplication) cell lines. In vitro, this combination led to decreased cell proliferation and increased apoptosis. The synergy translated in vivo in two different AML models, the SET-2 megakaryoblastic AML mouse model carrying a JAK2(V617F) mutation, and the MOLM-13 model of FLT3-ITD-driven AML. Pracinostat and pacritinib in combination showed synergy on tumor growth, reduction of metastases and synergistically decreased JAK2 or FLT signaling, depending on the cellular context. In addition, several plasma cytokines/growth factors/chemokines triggered by the tumor growth were normalized, providing a rationale for combination therapy with an HDACi and a JAK2/FLT3 inhibitor for the treatment of AML patients, particularly those with FLT3 or JAK2 mutations.