JAK2 inhibitors for myeloproliferative neoplasms: what is next?

Abstract

Since its approval in 2011, the Janus kinase 1/2 (JAK1/2) inhibitor ruxolitinib has evolved to become the centerpiece of therapy for myelofibrosis (MF), and its use in patients with hydroxyurea resistant or intolerant polycythemia vera (PV) is steadily increasing. Several other JAK2 inhibitors have entered clinical testing, but none have been approved and many have been discontinued. Importantly, the activity of these agents is not restricted to patients with JAK2 V617F or exon 12 mutations. Although JAK2 inhibitors provide substantial clinical benefit, their disease-modifying activity is limited, and rational combinations with other targeted agents are needed, particularly in MF, in which survival is short. Many such combinations are being explored, as are other novel agents, some of which could successfully be combined with JAK2 inhibitors in the future. In addition, new JAK2 inhibitors with the potential for less myelosuppression continue to be investigated. Given the proven safety and efficacy of ruxolitinib, it is likely that ruxolitinib-based combinations will be a major way forward in drug development for MF. If approved, less myelosuppressive JAK2 inhibitors such as pacritinib or NS-018 could prove to be very useful additions to the therapeutic armamentarium in MF. In PV, inhibitors of histone deacetylases and human double minute 2 have activity, but their role, if any, in the future treatment algorithm is uncertain, given the availability of ruxolitinib and renewed interest in interferons. Ruxolitinib is in late-phase clinical trials in essential thrombocythemia, in which it could fill an important void for patients with troublesome symptoms.

Figure 1.

Canonical and noncanonical actions of JAK2 and opportunities for therapeutic targeting. JAK2 transduces cytokine and growth factor signals from membrane-bound receptors through phosphorylation of the STAT family of transcription factors. Negative regulators of JAK2, such as LNK, CBL, and SOCS, lead to ubiquitinylation and proteasomal degradation of JAK2, whereas protein tyrosine phosphatases (PTPs) dephosphorylate cytokine receptors, JAKs, and STATs. The protein inhibitor of STATs (PIAS) prevents the binding of STATs to target DNA. JAK2 is a client of the chaperone protein HSP90, and HSP90 inhibitors and HDAC6 inhibitors (through acetylation and disruption of HSP90 function) promote degradation of JAK2. JAK2 signals downstream to the PI3K/Akt/mTOR and Ras/Raf/MEK/ERK signaling cascades, which provides opportunities for combined inhibition of JAK2 and PI3K, mTOR, or MEK1/2. BH3 mimetics promote mitochondrial apoptosis, and synergism with ruxolitinib in MPN cells and animal models has been shown. Synergism between ruxolitinib and the selective inhibitor of nuclear export selinexor has also been demonstrated preclinically. Activated JAK2 promotes cell cycle progression through several mechanisms discussed in the text, making combined inhibition of JAK2 and CDK4/6 a rational approach. Finally, nuclear JAK2 phosphorylates PRMT5 and histone H3, activating transcription of many genes, including those encoding the PIM kinases, Bcl-xL, D-type cyclins, the cell cycle phosphatase CDC25A, and SOCS (negative feedback). Epigenetic deregulation is frequent in MPNs, and combinations of ruxolitinib with epigenetic modifiers such as azacitidine and panobinostat have shown promise in the clinic. Combinations of ruxolitinib with immunomodulatory drugs are also being pursued. Adapted, with permission, from Meyer and Levine.