Codilupi, Tamara; Szybinski, Jakub; Arunasalam, Stefanie; Jungius, Sarah; Dunbar, Andrew C; Stivala, Simona; Brkic, Sime; Albrecht, Camille; Vokalova, Lenka; Yang, Julie L; Buczak, Katarzyna; Ghosh, Nilabh; Passweg, Jakob R; Rovo, Alicia; Angelillo-Scherrer, Anne; Pankov, Dmitry; Dirnhofer, Stephan; Levine, Ross L; Koche, Richard and Meyer, Sara C (2024). Development of resistance to type II JAK2 inhibitors in MPN depends on AXL kinase and is targetable. Clinical cancer research, 30(3), pp. 586-599. American Association for Cancer Research 10.1158/1078-0432.CCR-23-0163
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PURPOSE
Myeloproliferative neoplasms (MPN) dysregulate JAK2 signaling. Since clinical JAK2 inhibitors have limited disease-modifying effects, type II JAK2 inhibitors such as CHZ868 stabilizing inactive JAK2 and reducing MPN clones, gain interest. We studied whether MPN cells escape from type ll inhibition.
METHODS
MPN cells were continuously exposed to CHZ868. We used phosphoproteomic analyses and ATAC-/RNA-sequencing to characterize acquired resistance to type II JAK2 inhibition, and targeted candidate mediators in MPN cells and mice.
RESULTS
MPN cells showed increased IC50 and reduced apoptosis upon CHZ868 reflecting acquired resistance to JAK2 inhibition. Among >2500 differential phospho-sites, MAPK pathway activation was most prominent, while JAK2-STAT3/5 remained suppressed. Altered histone occupancy promoting AP-1/GATA binding motif exposure associated with upregulated AXL kinase and enriched RAS target gene profiles. AXL knockdown resensitized MPN cells and combined JAK2/AXL inhibition using bemcentinib or gilteritinib reduced IC50 to levels of sensitive cells. While resistant cells induced tumor growth in NSG mice despite JAK2 inhibition, JAK2/AXL inhibition largely prevented tumor progression. Since inhibitors of MAPK pathway kinases such as MEK are clinically used in other malignancies, we evaluated JAK2/MAPK inhibition with trametinib to interfere with AXL-MAPK-induced resistance. Tumor growth was halted similarly to JAK2/AXL inhibition and in a systemic cell line-derived mouse model, marrow infiltration was decreased supporting dependency on AXL-MAPK.
CONCLUSIONS
We report on a novel mechanism of AXL-MAPK-driven escape from type II JAK2 inhibition, which is targetable at different nodes. This highlights AXL as mediator of acquired resistance warranting inhibition to enhance sustainability of JAK2 inhibition in MPN.
Item Type: |
Journal Article (Original Article) |
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Division/Institute: |
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) 04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Haematology and Central Haematological Laboratory 04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Unit Childrens Hospital > Forschungsgruppe Hämatologie (Erwachsene) |
UniBE Contributor: |
Arunasalam, Stefanie, Jungius, Sarah, Albrecht, Camille, Rovó, Alicia, Angelillo, Anne, Meyer, Sara Christina |
Subjects: |
600 Technology > 610 Medicine & health |
ISSN: |
1078-0432 |
Publisher: |
American Association for Cancer Research |
Language: |
English |
Submitter: |
Pubmed Import |
Date Deposited: |
23 Nov 2023 09:49 |
Last Modified: |
02 Feb 2024 00:14 |
Publisher DOI: |
10.1158/1078-0432.CCR-23-0163 |
PubMed ID: |
37992313 |
BORIS DOI: |
10.48350/189292 |
URI: |
https://boris.unibe.ch/id/eprint/189292 |
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