Pharmacological Modulation of the Crosstalk between Aberrant Janus Kinase Signaling and Epigenetic Modifiers of the Histone Deacetylase Family to Treat Cancer

Janus kinase (JAK) sig-naling is an appreciated drug target in human cancers. Numerous mutant JAK molecules as well as inherent and acquired drug resistance mechanisms limit the effi-cacy of JAK inhibitors (JAKi). There is accumulating evidence that epigenetic mechanisms control JAK-dependent signaling cascades. Like JAKs, epigenetic modifiers of the histone deacetylase (HDAC) family regulate the growth and development of cells and are often dysregulated in cancer cells. The notion that inhibitors of histone deacetylases (HDACi) ab-rogate oncogenic JAK-dependent signaling cascades illustrates an intricate crosstalk between JAKs and HDACs. Here, we summarize how structurally divergent, broad-acting as well as isoenzyme-spe-cific HDACi, hybrid fusion pharmacophores contain-ing JAKi and HDACi, and proteolysis targeting chimeras for JAKs inactivate the four JAK proteins JAK1, JAK2, JAK3, and tyrosine kinase-2. These agents suppress aberrant JAK activity through specific tran-scription-dependent processes and mechanisms that alter the phosphorylation and stability of JAKs. Pharma-cological inhibition of HDACs abrogates allosteric acti-vation of JAKs, overcomes limitations of ATP -competitive type 1 and type 2 JAKi, and interacts favor-ably with JAKi. Since such findings were collected in cultured cells, experimental animals, and cancer pa-tients, we condense preclinical and translational rele-vance. We also discuss how future research on acetylation-dependent mechanisms that regulate JAKs might allow the rational design of improved treatments for cancer patients.Significance Statement--Reversible lysine -E-N acet-ylation and deacetylation cycles control phosphoryla-tion-dependent Janus kinase-signal transducer and activator of transcription signaling. The intricate crosstalk between these fundamental molecular mech-anisms provides opportunities for pharmacological in-tervention strategies with modern small molecule inhibitors. This could help patients suffering from cancer.