Targeting compensatory MEK/ERK activation increases JAK inhibitor efficacy in myeloproliferative neoplasms.

Stivala, Simona; Codilupi, Tamara; Brkic, Sime; Baerenwaldt, Anne; Ghosh, Nilabh; Hao-Shen, Hui; Dirnhofer, Stephan; Dettmer, Matthias S.; Simillion, Cedric; Kaufmann, Beat A; Chiu, Sophia; Keller, Matthew; Kleppe, Maria; Hilpert, Morgane; Buser, Andreas S; Passweg, Jakob R; Radimerski, Thomas; Skoda, Radek C; Levine, Ross L and Meyer, Sara C (2019). Targeting compensatory MEK/ERK activation increases JAK inhibitor efficacy in myeloproliferative neoplasms. The journal of clinical investigation, 129(4), pp. 1596-1611. American Society for Clinical Investigation 10.1172/JCI98785

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute of Pathology

UniBE Contributor:

Dettmer, Matthias

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

1558-8238

Publisher:

American Society for Clinical Investigation

Language:

English

Submitter:

Matthias Dettmer

Date Deposited:

25 Sep 2019 10:39

Last Modified:

23 Oct 2019 07:55

Publisher DOI:

10.1172/JCI98785

PubMed ID:

30730307

Uncontrolled Keywords:

Hematology Leukemias Oncology

BORIS DOI:

10.7892/boris.133287

URI:

https://boris.unibe.ch/id/eprint/133287

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