Abstract
CHZ868 inhibits the proliferation of JAK2-mutant and type I JAK inhibitor–persistent cells.
Major finding: CHZ868 inhibits the proliferation of JAK2-mutant and type I JAK inhibitor–persistent cells.
Concept: Type II JAK2 inhibitors stabilize the inactive kinase conformation and improve target inhibition.
Impact: CHZ868 treatment may have benefit in JAK2-driven B-ALL and myeloproliferative neoplasms.
The discovery of mutations that drive activation of oncogenic JAK–STAT signaling in myeloproliferative neoplasms (MPN) and B-cell acute lymphoblastic leukemia (B-ALL) has led to the clinical development of JAK kinase inhibitors. Despite initial success, long-term clinical response to type I JAK kinase inhibitors, such as ruxolitinib, has been limited by adaptive resistance that drives persistent JAK–STAT reactivation. To improve the efficacy of JAK2 kinase inhibition, Meyer and colleagues tested the efficacy of the type II JAK2 inhibitor CHZ868 in models of JAK-driven MPN. CHZ868 selectively inhibited the growth of JAK2-mutant cells and type I JAK inhibitor–persistent cells by stabilizing JAK2 in an inactive conformation that prevents JAK2 transphosphorylation in heterodimers and suppresses downstream JAK–STAT signaling. CHZ868 treatment decreased mutant allele burden, inhibited myeloproliferation, reversed disease characteristics, and increased overall survival in murine models of JAK2-dependent polycythemia vera and primary myelofibrosis. Consistent with these findings, Wu, Li, Kopp, and colleagues confirmed that CHZ868 potently inhibited JAK2 signaling and suppressed the growth of JAK2-dependent B-ALL cells in vitro. In addition, CHZ868 treatment in B-ALL patient-derived xenograft models induced apoptosis, downregulated the expression of cell-cycle regulators such as MYC, and synergized with dexamethasone, a standard-of-care B-ALL chemotherapy, to decrease proliferation and promote B-ALL cell death. Indeed, combination treatment with CHZ868 and dexamethasone reduced tumor burden and increased overall survival in murine models of B-ALL. Furthermore, a mutagenesis screen highlighted the L884P mutation in JAK2, which was hypothesized to confer resistance to type II JAK2 inhibitors by disrupting inhibitor binding based on structural modeling. Together, these results provide a rationale for the use of type II JAK2 inhibitors as a single agent or in combination with dexamethasone in leukemias and other malignancies driven by JAK2 signaling, including those that are resistant to type I JAK inhibitors.
