Targeting compensatory MEK/ERK activation increases JAK inhibitor efficacy in myeloproliferative neoplasms Journal Article
| Authors: | Stivala, S.; Codilupi, T.; Brkic, S.; Baerenwaldt, A.; Ghosh, N.; Hao-Shen, H.; Dirnhofer, S.; Dettmer, M. S.; Simillion, C.; Kaufmann, B. A.; Chiu, S.; Keller, M.; Kleppe, M.; Hilpert, M.; Buser, A. S.; Passweg, J. R.; Radimerski, T.; Skoda, R. C.; Levine, R. L.; Meyer, S. C. |
| Article Title: | Targeting compensatory MEK/ERK activation increases JAK inhibitor efficacy in myeloproliferative neoplasms |
| Abstract: | Constitutive JAK2 signaling is central to myeloproliferative neoplasm (MPN) pathogenesis and results in activation of STAT, PI3K/AKT, and MEK/ERK signaling. However, the therapeutic efficacy of current JAK2 inhibitors is limited. We investigated the role of MEK/ERK signaling in MPN cell survival in the setting of JAK inhibition. Type I and II JAK2 inhibition suppressed MEK/ERK activation in MPN cell lines in vitro, but not in Jak2V617F and MPLW515L mouse models in vivo. JAK2 inhibition ex vivo inhibited MEK/ERK signaling, suggesting that cell-extrinsic factors maintain ERK activation in vivo. We identified PDGFRα as an activated kinase that remains activated upon JAK2 inhibition in vivo, and PDGF-AA/PDGF-BB production persisted in the setting of JAK inhibition. PDGF-BB maintained ERK activation in the presence of ruxolitinib, consistent with its function as a ligand-induced bypass for ERK activation. Combined JAK/MEK inhibition suppressed MEK/ERK activation in Jak2V617F and MPLW515L mice with increased efficacy and reversal of fibrosis to an extent not seen with JAK inhibitors. This demonstrates that compensatory ERK activation limits the efficacy of JAK2 inhibition and dual JAK/MEK inhibition provides an opportunity for improved therapeutic efficacy in MPNs and in other malignancies driven by aberrant JAK-STAT signaling. |
| Keywords: | oncology; hematology; leukemias |
| Journal Title: | Journal of Clinical Investigation |
| Volume: | 129 |
| Issue: | 4 |
| ISSN: | 0021-9738 |
| Publisher: | American Society for Clinical Investigation |
| Date Published: | 2019-04-01 |
| Start Page: | 1596 |
| End Page: | 1611 |
| Language: | English |
| DOI: | 10.1172/jci98785 |
| PUBMED: | 30730307 |
| PROVIDER: | scopus |
| PMCID: | PMC6436863 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 April 2019 -- Source: Scopus |
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