PreprintArticleVersion 1Preserved in Portico This version is not peer-reviewed
Type II JAK2 Inhibitor CHZ‐868 and HSP90 Inhibitors Are Potent towards the Ruxolitinib Resistant JAK2 Variants in JAK2 Driven Myeloproliferative Neoplasms
Version 1
: Received: 29 December 2023 / Approved: 3 January 2024 / Online: 3 January 2024 (14:39:52 CET)
How to cite:
Gorantla, S.P.; Prince, G.; Osius, J.; Dinesh, D.; Boddu, V.K.; Duyster, J.; Von Bubnoff, N. Type II JAK2 Inhibitor CHZ‐868 and HSP90 Inhibitors Are Potent towards the Ruxolitinib Resistant JAK2 Variants in JAK2 Driven Myeloproliferative Neoplasms. Preprints2024, 2024010265. https://doi.org/10.20944/preprints202401.0265.v1
Gorantla, S.P.; Prince, G.; Osius, J.; Dinesh, D.; Boddu, V.K.; Duyster, J.; Von Bubnoff, N. Type II JAK2 Inhibitor CHZ‐868 and HSP90 Inhibitors Are Potent towards the Ruxolitinib Resistant JAK2 Variants in JAK2 Driven Myeloproliferative Neoplasms. Preprints 2024, 2024010265. https://doi.org/10.20944/preprints202401.0265.v1
Gorantla, S.P.; Prince, G.; Osius, J.; Dinesh, D.; Boddu, V.K.; Duyster, J.; Von Bubnoff, N. Type II JAK2 Inhibitor CHZ‐868 and HSP90 Inhibitors Are Potent towards the Ruxolitinib Resistant JAK2 Variants in JAK2 Driven Myeloproliferative Neoplasms. Preprints2024, 2024010265. https://doi.org/10.20944/preprints202401.0265.v1
APA Style
Gorantla, S.P., Prince, G., Osius, J., Dinesh, D., Boddu, V.K., Duyster, J., & Von Bubnoff, N. (2024). Type II JAK2 Inhibitor CHZ‐868 and HSP90 Inhibitors Are Potent towards the Ruxolitinib Resistant JAK2 Variants in JAK2 Driven Myeloproliferative Neoplasms. Preprints. https://doi.org/10.20944/preprints202401.0265.v1
Chicago/Turabian Style
Gorantla, S.P., Justus Duyster and Nikolas Von Bubnoff. 2024 "Type II JAK2 Inhibitor CHZ‐868 and HSP90 Inhibitors Are Potent towards the Ruxolitinib Resistant JAK2 Variants in JAK2 Driven Myeloproliferative Neoplasms" Preprints. https://doi.org/10.20944/preprints202401.0265.v1
Abstract
Ruxolitinib has been approved by FDA for the treatment of myeloproliferative neoplasms such as polycythemia vera and idiopathic myelofibrosis. Although ruxolitinib has been in the clinic for more than ten years, surprisingly, no JAK2 drug resistant mutations have been identified in patients. At the moment, it is not clear whether the absence of JAK2 mutations in MPN patients is due to a lack of JAK2 addiction or residues that mediate the drug resistance compromising the JAK2 function. To find out this, we established a Ba/F3 cell-based screening strategy to predict mutations in JAK2-V617F that cause resistance towards ruxolitinib. In this study, we have recovered seven residues in the kinase domain of JAK2 that affect ruxolitinib sensitivity. All these mutations confer cross-resistance across the panel of JAK2 kinase inhibitors except JAK2-L983F. JAK2-L983F reduces the sensitivity towards ruxolitinib. However, it is sensitive towards fedratinib indicating that our screen identifies the drug-specific resistance profiles. All the ruxolitinib resistant JAK2 variants displayed sensitivity towards Type II JAK2 inhibitor CHZ-868. Finally, our study also shows that HSP90 inhibitors are potent against ruxolitinib resistant variants through the JAK2 degradation and provides the rationale for clinical evaluation of potent HSP90 inhibitors in genetic resistance driven by JAK2 inhibitors.
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
,
,
