The mechanism of resistance to JAK2 inhibitor in myeloproliferative neoplasms patients


The gain-of-function mutation in the gene encoding Janus kinase 2 (JAK2) is frequently found in patients with myeloproliferative neoplasms (MPNs). Those patients performed resistent to therapy that targeting JAK and its downstream signaling, such as signal transducer and activator of transcription (STAT). Winter et al. identified the underlying mechanism of the emerging therapy resistance, and found the guanosine triphosphatase (GTPase) RAS and pathways mediated by AKT and ERK contribute to the resistance. The article was published in Science Signaling.


Reaserchers performed pathway-centric screens in hematopoietic cells containing JAK2V617F mutation, found GTPase RAS and its effector pathways mediated by AKT and ERK are involved in generation of resistance to JAK inhibition. Mechanistically, the JAK2 mediated phosphorylation inactivates B cell lymphoma 2-associated death promoter (BAD), which regulates cell apoptosis, to promote cell growth and proliferation. In sensitive cells, BAD is activated by JAK inhibitor-induced dephosphorylation. However, in insensitive cells, RAS effector signaling maintains BAD phosphorylation after being treated by JAK inhibitors. The gain-of-function mutations in RAS and JAK2V617F mutation in MPNs cells further suggest RAS effector pathways are critical in mediating targeted therapy resistance. The combination therapies of JAK inhibitors with AKT, MEK or ERK inhibitors held promising cilinical stretagies in against MPNs.


Sci Signal. 2014 Dec 23;7(357):ra122.

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