Genetic resistance to JAK2 enzymatic inhibitors is overcome by HSP90 inhibition

Weigert, Oliver; Lane, Andrew A.; Bird, Liat; Kopp, Nadja; Chapuy, Bjoern; Bodegom, Diederik van; Toms, A.V.; Marubayashi, Sachie; Christie, Amanda L.; McKeown, M.; Paranal, Ronald M.; Bradner, James E.; Yoda, Akinori; Gaul, Christoph; Vangrevelinghe, Eric; Romanet, Vincent; Murakami, Masato; Tiedt, Ralph; Ebel, Nicolas; Evrot, Emeline; Pover, Alain De; Régnier, Catherine H.; Erdmann, Dirk; Hofmann, Francesco; Eck, Michael J.; Sallan, Stephen E.; Levine, Ross L.; Kung, Andrew L.; Baffert, Fabienne; Radimerski, Thomas; Weinstock, David M.

doi:10.1084/jem.20111694

Cited by 151 publications

(191 citation statements)

References 55 publications

(88 reference statements)

Supporting

Mentioning

175

Contrasting

Unclassified

Order By: Relevance

“…3A). Multiple JAK2 inhibitors have been previously reported to show similar results where they directly target JAK2 but increase or do not affect JAK2 phosphorylation levels (44,45). GinA markedly inhibited S6 phosphorylation dose-dependently in both EJ and HCT116 cells (Fig.…”

Section: Resultsmentioning

confidence: 54%

See 1 more Smart Citation

Identification of a Dual Inhibitor of Janus Kinase 2 (JAK2) and p70 Ribosomal S6 Kinase1 (S6K1) Pathways

Byun

Lim

Mun

et al. 2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: An underlying cause of cancer therapeutic resistance is the hyperactivation of endogenous overlapping or redundant signaling pathways in cancer cells. Results: Gingerenone A selectively kills cancer cells through dual inhibition of JAK2 and S6K1. Conclusion: Co-targeting JAK2 and S6K1 induces synergistic anti-cancer effects. Significance: Investigating the targets of bioactive compounds can lead to suggestions for novel therapeutic strategies.

show abstract

Section: Resultsmentioning

confidence: 54%

“…Previous studies have also reported multiple JAK2 inhibitors that maintained or increased the phosphorylation levels of JAK2 (44,45). In addition, inhibitors for other kinases have been shown to not affect the phosphorylation levels of the target kinase, whereas the activity was inhibited by the compounds (51)(52)(53).…”

Section: Discussionmentioning

confidence: 94%

Identification of a Dual Inhibitor of Janus Kinase 2 (JAK2) and p70 Ribosomal S6 Kinase1 (S6K1) Pathways

Byun

Lim

Mun

et al. 2015

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Furthermore, Hsp90 is a promising therapeutic target also in JAK-2 driven cancer, e.g., myeloproliferative neoplasms, B cell acute lymphoblastoid leukemia, including those with genetic resistance to JAK enzymatic inhibitors (122,123). Intriguingly, Hsp90 inhibitor-based antileukemia therapy may override de novo or acquired resistance of acute myelogenous leukemia cells to pan-histone deacetylase inhibitors (124).…”

Section: Combination Of Hsp90 Inhibitor With Second Therapymentioning

confidence: 99%

Hsp90 inhibitor as a sensitizer of cancer cells to different therapies (Review)

Solárová¹,

Mojžiš²,

Solár³

2014

Int J Oncol

View full text Add to dashboard Cite

Abstract. Hsp90 is a molecular chaperone that maintains the structural and functional integrity of various client proteins involved in signaling and many other functions of cancer cells. The natural inhibitors, ansamycins influence the Hsp90 chaperone function by preventing its binding to client proteins and resulting in their proteasomal degradation. Nand C-terminal inhibitors of Hsp90 and their analogues are widely tested as potential anticancer agents in vitro, in vivo as well as in clinical trials. It seems that Hsp90 competitive inhibitors target different tumor types at nanomolar concentrations and might have therapeutic benefit. On the contrary, some Hsp90 inhibitors increased toxicity and resistance of cancer cells induced by heat shock response, and through the interaction of survival signals, that occured as side effects of treatments, could be very effectively limited via combination of therapies. The aim of our review was to collect the data from experimental and clinical trials where Hsp90 inhibitor was combined with other therapies in order to prevent resistance as well as to potentiate the cytotoxic and/or antiproliferative effects.

show abstract

“…Indeed, in the same studies, cytotoxicity assays show that the cells having the resistant mutations were more sensitive than WT cells to HSP90 inhibition using AUY22. 101 Similarly, inhibition of HSP90 activity has also been shown to be effective in cases where cells are able to overcome Jak2 inhibition and sustain aberrant JAK/ STAT signaling by co-opting other kinases to trans-activate Jak2. 102 These examples, while not exhaustive, highlight the importance of HSP90 in the development and maintenance of many pathological states mediated by aberrant JAK/STAT signaling, including both solid and hematologic malignancies, 99 along with the therapeutic potential of pharmacological inhibition HSP90 as potential treatment for such malignancies.…”

Section: Jak Kinases and Chaperonesmentioning

confidence: 99%

Contribution of chaperones to STAT pathway signaling

et al. 2014

View full text Add to dashboard Cite

Aberrant STAT signaling is associated with the development and progression of many cancers and immune related diseases. Recent findings demonstrate that proteostasis modulators under clinical investigation for cancer therapy have a significant impact on STAT signaling, which may be critical for mediating their anti-cancer effects. Chaperones are critical for protein folding, stability and function and, thus, play an essential role in the maintenance of proteostasis. In this review we discuss the role of chaperones in STAT and tyrosine kinase (TK) protein folding, modulation of STAT and TK activity, and degradation of TKs. We highlight the important role of chaperones in STAT signaling, and how this knowledge has provided a framework for the development of new therapeutic avenues of targeting STAT signaling related pathologies.

show abstract

Genetic resistance to JAK2 enzymatic inhibitors is overcome by HSP90 inhibition

Abstract: Hsp90 inhibition in B cell acute lymphoblastic leukemia overcomes resistance to JAK2 inhibitors.

Cited by 151 publications

References 55 publications

Identification of a Dual Inhibitor of Janus Kinase 2 (JAK2) and p70 Ribosomal S6 Kinase1 (S6K1) Pathways

Identification of a Dual Inhibitor of Janus Kinase 2 (JAK2) and p70 Ribosomal S6 Kinase1 (S6K1) Pathways

Hsp90 inhibitor as a sensitizer of cancer cells to different therapies (Review)

Contribution of chaperones to STAT pathway signaling

Contact Info

Product

Resources

About