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

Acute myeloid leukemia (AML) is typically treated with aggressive chemotherapy, which is often poorly tolerated by elderly patients. This highlights the urgent need for more effective therapies that are less toxic and better tolerated. Several targeted agents, including inhibitors of FMS-like tyrosine kinase 3 (FLT3), Janus kinase 2 (JAK2), and histone deacetylase inhibitors (HDACi), have been evaluated in clinical trials.

However, these agents have shown limited single-agent activity. Notably, the HDACi pracinostat has demonstrated high efficacy in treating AML and exhibits synergy when combined with the JAK2/FLT3 inhibitor pacritinib. Both compounds suppress JAK-signal transducer and activator of transcription (STAT) signaling in AML cells harboring JAK2(V617F) mutations. They also reduce FLT3 signaling, especially in FLT3-internal tandem duplication (FLT3-ITD) cell lines. In vitro studies revealed that this combination reduces cell proliferation and enhances apoptosis.

The synergistic effect was confirmed in two distinct AML mouse models: the SET-2 megakaryoblastic AML model with a JAK2(V617F) mutation and the MOLM-13 model of FLT3-ITD-driven AML. When combined, pracinostat and pacritinib exhibited synergy in inhibiting tumor growth, reducing metastases, and suppressing JAK2 or FLT3 signaling, depending on the specific genetic context of the cells. Furthermore, the treatment normalized several plasma cytokines, growth factors, and chemokines that are typically elevated due to tumor growth. These findings provide a strong rationale for combining an HDACi with a JAK2/FLT3 inhibitor as a therapeutic approach for AML patients, particularly those with FLT3 or JAK2 mutations.