HSP90 is a therapeutic target in JAK2-dependent myeloproliferative neoplasms in mice and humans

Abstract

JAK2 kinase inhibitors were developed for the treatment of myeloproliferative neoplasms (MPNs), following the discovery of activating JAK2 mutations in the majority of patients with MPN. However, to date JAK2 inhibitor treatment has shown limited efficacy and apparent toxicities in clinical trials. We report here that an HSP90 inhibitor, PU-H71, demonstrated efficacy in cell line and mouse models of the MPN polycythemia vera (PV) and essential thrombocytosis (ET) by disrupting JAK2 protein stability. JAK2 physically associated with both HSP90 and PU-H71 and was degraded by PU-H71 treatment in vitro and in vivo, demonstrating that JAK2 is an HSP90 chaperone client. PU-H71 treatment caused potent, dose-dependent inhibition of cell growth and signaling in JAK2 mutant cell lines and in primary MPN patient samples. PU-H71 treatment of mice resulted in JAK2 degradation, inhibition of JAK-STAT signaling, normalization of peripheral blood counts, and improved survival in MPN models at doses that did not degrade JAK2 in normal tissues or cause substantial toxicity. Importantly, PU-H71 treatment also reduced the mutant allele burden in mice. These data establish what we believe to be a novel therapeutic rationale for HSP90 inhibition in the treatment of JAK2-dependent MPN.

Targeting HSP90 Ameliorates Nephropathy and Atherosclerosis Through Suppression of NF-κB and STAT Signaling Pathways in Diabetic Mice

“…Owing to its chaperoning function, HSP90 regulates the stability and the activation of NF-kB and STAT signaling pathways by direct association and stabilization of their respective activating kinases, IKK (42) and JAK2 (43). Accordingly, the efficacy of HSP90 inhibitors in animal models has been linked to the disruption of the IKK complex and JAK2 protein stability, further inhibiting downstream transcription factors such as p50/p65 NF-kB (44) and STAT1/STAT3/STAT5 (45).…”

Heat Shock Protein 90 Functions to Stabilize and Activate the Testis-specific Serine/Threonine Kinases, a Family of Kinases Essential for Male Fertility

“…HSP90 is a ubiquitously expressed protein that is involved in native folding, stabilization, maturation, and activation of numerous cellular proteins (14,15,20). Several natural products as well as synthetic compounds inhibit HSP90 function by occupying its ATP binding pocket (21) and lead to destabilization of the client proteins including kinases, transcription factors, steroid receptors, and others such as the fibrosis transmembrane conductance regulator and huntingtin (19, 21, 24 -32).…”

“…Unlike the other major classes of HSPs, HSP90 preferentially interacts with a specific subset of proteins and is involved with maturation of signaling molecules including protein kinases, transcription factors, and hormone receptors (14,15). HSP90 possesses an intrinsic ATPase activity that is required for mediating the necessary conformational changes in client proteins for activation (15,17,18) and is also important for stabilization of the HSP90 client proteins (19,20). HSP90 inhibitors 17-allylamino-17-demethoxygeldanamycin (17-AAG) as well as other structurally distinct agents, including SNX-5422 (also known as PF-04929113) and NVP-AUY922, bind to the nucleotide binding pocket of HSP90 and inhibit the progression of the HSP90 complex toward the stabilizing form resulting in the degradation of the client proteins (16,19,(21)(22)(23).…”

Repeated PD-1/PD-L1 monoclonal antibody administration induces fatal xenogeneic hypersensitivity reactions in a murine model of breast cancer

“…6A). 23,43 In contrast to mice receiving anti-PD-1 as a monotherapy, mice receiving anti-PD-1 in combination with ganetespib were able to survive the full course of the combination regimen before eventually succumbing to primary tumor burden (Fig. 6B).…”