Crizotinib Has Preclinical Efficacy in Philadelphia-Negative Myeloproliferative Neoplasms

Purpose: The Philadelphia chromosome-negative myeloprolif-erative neoplasms (MPN) polycythemia vera, essential thrombo-cythemia, and primary myelofibrosis are characterized by JAK/ STAT pathway activation. JAK inhibitors are approved for MPN treatment, but persistence has been observed, due to JAK/STAT reactivation. Experimental Design: Using MPN patient samples, JAK2-mutated cell lines, and MPN mouse models, we examined both the efficacy and mechanism by which crizotinib, the ALK/ MET/RON/ROS1 inhibitor approved for the treatment of non- small cell lung cancer, alters MPN cell proliferation and JAK/STAT activation. Results: We found that crizotinib suppresses proliferation and activation of JAK/STAT signaling, and decreases the disease burden in the JAK2V617F mouse model of MPN. Furthermore, we found that crizotinib could overcome JAK inhibitor persistence to ruxolitinib. Interestingly, phosphorylation of the crizotinib target RON kinase was enhanced in ruxolitinib-persistent cells. We show that phospho-JAK2 and phospho-RON can physically interact to sustain JAK/STAT signaling, and that the combination of crizotinib and ruxolitinib disrupts this interaction. Furthermore, RON knock-down suppresses proliferation and activation of JAK/STAT signal -ing in JAK2-mutated cells, and RON deletion in a JAK2V617F mouse MPN model decreases the disease burden. We also observed RON hyperactivation in MPN patient cells, suggesting that RON may be an important target of crizotinib in MPN. Conclusions: In summary, we demonstrate that crizotinib has preclinical efficacy in MPN patient cells, JAK2-mutated cell lines, and a JAK2-mutated mouse model, and that the combination of crizotinib with JAK inhibitors suppresses JAK inhibitor persistence. Our work suggests that crizotinib should be investigated for the treatment of patients with MPN.

Automated summary

The study found that crizotinib could suppress the activation of the JAK/STAT signaling pathway and decrease the disease burden of MPN. Additionally, crizotinib could overcome the persistence of JAK inhibitors by disrupting the interaction between RON kinase and JAK2. This research suggests that crizotinib should be further explored as a potential treatment for patients with MPN.