Development of Resistance to Type II JAK2 Inhibitors in MPN Depends on AXL Kinase and Is Targetable

Area of Science:

• Hematology
• Oncology
• Molecular Biology

Background:

• Myeloproliferative neoplasms (MPN) are characterized by dysregulated Janus kinase 2 (JAK2) signaling.
• Current JAK2 inhibitors have limited disease-modifying capacity.
• Type II JAK2 inhibitors, like CHZ868, stabilize inactive JAK2 and show promise in reducing MPN clones.

Purpose of the Study:

• To investigate whether MPN cells can acquire resistance to type II JAK2 inhibition.
• To elucidate the molecular mechanisms underlying acquired resistance to type II JAK2 inhibitors.
• To identify potential therapeutic strategies to overcome JAK2 inhibitor resistance in MPN.

Main Methods:

• Continuous exposure of MPN cells to CHZ868.
• Phosphoproteomic analysis, ATAC-seq, and RNA-seq to characterize resistance mechanisms.
• In vitro and in vivo studies using MPN cell lines and mouse models.
• Targeted inhibition of identified resistance mediators, including AXL and MAPK pathway kinases.

Main Results:

• MPN cells developed resistance to CHZ868, evidenced by increased IC50 and reduced apoptosis.
• Acquired resistance was associated with activation of the MAPK pathway, not JAK2-STAT3/5 signaling.
• Upregulation of AXL kinase and enrichment of RAS target genes were observed, linked to altered histone occupancy.
• Combined JAK2/AXL inhibition or JAK2/MAPK inhibition resensitized resistant cells and significantly reduced tumor growth in vivo.
• AXL inhibition was identified as a key mediator of acquired resistance.

Conclusions:

• A novel mechanism of AXL/MAPK-driven escape from type II JAK2 inhibition in MPN was identified.
• AXL acts as a crucial mediator of acquired resistance to JAK2 inhibitors.
• Targeting AXL or the MAPK pathway in combination with JAK2 inhibitors offers a promising strategy to enhance treatment efficacy and sustainability in MPN.