Combination treatment for myeloproliferative neoplasms using JAK and pan-class I PI3K inhibitors

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Current Janus Kinase 2 (JAK2) inhibitors for myeloproliferative neoplasms (MPNs) lack specificity, impacting normal physiological signaling.
• Aberrant JAK2 signaling is a key driver in MPNs, necessitating targeted therapeutic approaches.

Purpose of the Study:

• To investigate the synergistic effects of combining JAK2 inhibitors with various serine/threonine kinase inhibitors in preclinical models of MPNs.
• To identify specific kinase inhibitor combinations that selectively target mutant JAK2 signaling.

Main Methods:

• Screening of 15 kinase inhibitors in combination with JAK2 inhibitors against hematopoietic cells expressing mutant JAK2 (V617F) or thrombopoietin receptor (W515L).
• Utilizing Chou and Talalay analysis to quantify synergistic inhibition.
• Evaluating the efficacy of the optimal drug combination (ruxolitinib and GDC0941) in a mouse model and patient-derived cells.

Main Results:

• ZSTK474, a phosphatydylinositol-3'-kinase (PI3K) inhibitor, demonstrated strong synergy with JAK2 and JAK2/JAK1 inhibitors.
• Pan-class I PI3K inhibitors, but not gamma or delta specific ones, showed synergistic effects with JAK2 inhibitors.
• The combination of ruxolitinib and GDC0941 reduced spleen weight in mice and inhibited erythroid colony formation from MPN patients and mice, with preferential targeting of JAK2 V617F mutated progenitors.

Conclusions:

• Combination therapy with JAK2 and pan-class I PI3K inhibitors offers a synergistic approach for MPN treatment.
• This strategy shows potential for selectively inhibiting malignant JAK2 signaling while sparing normal physiological pathways.
• The findings support the clinical investigation of combined JAK2 and pan-class I PI3K inhibition in MPN patients.