Molecular pathways: molecular basis for sensitivity and resistance to JAK kinase inhibitors

Abstract

Janus-activated kinases (JAK) are the mediators of a variety of cytokine signals via their cognate receptors that result in activation of intracellular signaling pathways. Alterations in JAK1, JAK2, JAK3, and TYK2 signaling contribute to different disease states, and dysregulated JAK-STAT signaling is associated with hematologic malignancies, autoimmune disorders, and immune-deficient conditions. Genetic alterations of JAK2 occur in the majority of patients with myeloproliferative neoplasms and occur in a subset of patients with acute leukemias. JAK-mediated signaling critically relies on STAT transcription factors, and on activation of the MAPK and PI3K/Akt signaling axes. Hyperactive JAK at the apex of these potent oncogenic signaling pathways therefore represents an important target for small-molecule kinase inhibitors in different disease states. The JAK1/2 inhibitor ruxolitinib and the JAK3 inhibitor tofacitinib were recently approved for the treatment of myelofibrosis and rheumatoid arthritis, respectively, and additional ATP-competitive JAK inhibitors are in clinical development. Although these agents show clinical activity, the ability of these JAK inhibitors to induce clinical/molecular remissions in hematologic malignancies seems limited and resistance upon chronic drug exposure is seen. Alternative modes of targeting JAK2 such as allosteric kinase inhibition or HSP90 inhibition are under evaluation, as is the use of histone deacetylase inhibitors. Combination therapy approaches integrating inhibition of STAT, PI3K/Akt, and MAPK pathways with JAK kinase inhibitors might be critical to overcome malignancies characterized by dysregulated JAK signaling.

Figure 1. Overview of molecular JAK signaling

Ligand binding to cell surface cytokine receptors initiates autophosphorylation of JAK2 and phosphorylation of cytoplasmic receptor tyrosines. STATs bind receptor phosphotyrosines via SH2 domains and translocate to the nucleus to induce expression of effector genes such as anti-apoptotic Pim kinase and BclxL, cyclins promoting cell cycle progression and SOCS forming a negative feedback loop. JAK2 also activates the PI3K/Akt and the MAPK pathways promoting proliferation and survival. Nuclear JAK2 is involved in epigenetic modifications. The negative regulators SOCS and CBL mark JAK2 for proteasomal degradation, LNK sequesters JAK2 by direct binding, and protein tyrosine phosphatases (PTP) dephosphorylate cytokine receptors, JAK and STATs. The protein inhibitors of STATs (PIAS) prevent STATs from binding target DNA. Stars indicate signaling components with reported genetic alterations. Transcription factors are shown in blue, negative regulators in green. MF myelofibrosis, ET essential thrombocythemia, PV polycythemia vera, CMML chronic myelomonocytic leukemia, MDS myelodysplastic syndrome, AML acute myeloid leukemia, ALL acute lymphatic leukemia, MPN myeloproliferative neoplasms, aCML atypical chronic myeloid leukemia, HD Hodgkin disease, NHL non hodgkin lymphoma, LGL large granular lymphocyte leukemia.