Crizotinib Has Preclinical Efficacy in Philadelphia-Negative Myeloproliferative Neoplasms

Lindsay M. Gurska, Rachel Okabe, Alexandra Schurer, Meng Maxine Tong, Mark Soto, Daniel Choi, Kristina Ames, Shira Glushakow-Smith, Allison Montoya, Ellen Tein, Linde A. Miles, Haiying Cheng, Pamela Hankey-Giblin, Ross L. Levine, Swati Goel, Balazs Halmos, Kira Gritsman

Research output: Contribution to journalArticlepeer-review


PURPOSE: The Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) polycythemia vera, essential thrombocythemia, 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 knockdown suppresses proliferation and activation of JAK/STAT signaling 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.

Original languageEnglish (US)
Pages (from-to)943-956
Number of pages14
JournalClinical Cancer Research
Issue number5
StatePublished - Mar 1 2023

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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