Category

Archives

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.

 

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

Related Products

Cat.No. Product Name Information Publications Customer Product Validation
S1078 MK-2206 2HCl MK-2206 2HCl is a highly selective inhibitor of Akt1/2/3 with IC50 of 8 nM/12 nM/65 nM in cell-free assays, respectively; no inhibitory activities against 250 other protein kinases observed. Phase 2. (682) (21)
S1008 Selumetinib (AZD6244) Selumetinib (AZD6244) is a potent, highly selective MEK inhibitor with IC50 of 14 nM for MEK1 and Kd value of 530 nM for MEK2. It also inhibits ERK1/2 phosphorylation with IC50 of 10 nM, no inhibition to p38α, MKK6, EGFR, ErbB2, ERK2, B-Raf, etc. Phase 3. (230) (14)
S1009 Dactolisib (BEZ235, NVP-BEZ235) Dactolisib (BEZ235, NVP-BEZ235) is a dual ATP-competitive PI3K and mTOR inhibitor for p110α/γ/δ/β and mTOR(p70S6K) with IC50 of 4 nM /5 nM /7 nM /75 nM /6 nM in cell-free assays, respectively. Inhibits ATR with IC50 of 21 nM in 3T3TopBP1-ER cell. (209) (11)
S2198 SGI-1776 free base SGI-1776 free base is a novel ATP competitive inhibitor of Pim1 with IC50 of 7 nM in a cell-free assay, 50- and 10-fold selective versus Pim2 and Pim3, also potent to Flt3 and haspin. Phase 1. (11) (3)

Related Targets