Research ArticleCancer

RAS signaling promotes resistance to JAK inhibitors by suppressing BAD-mediated apoptosis

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Science Signaling  23 Dec 2014:
Vol. 7, Issue 357, pp. ra122
DOI: 10.1126/scisignal.2005301

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Overcoming Resistance in Bone Marrow Cancer

An activating mutation in the kinase JAK2 (Janus kinase 2) is common in patients with myeloproliferative neoplasms (MPNs), which are abnormal growths of cells in the bone marrow that may progress to acute myeloid leukemia. However, cells often show inherent resistance to clinically used JAK inhibitors. Using a pathway-centric screen described by Martz et al. in this issue, Winter et al. found that the pathway mediated by RAS, another protein that is frequently activated in MPNs and numerous other cancers, promoted resistance in hematopoietic cell lines containing an activating mutation in JAK2. RAS signaling led to the phosphorylation-mediated inactivation of the death-promoting (proapoptotic) protein BAD, enabling cell survival. Combining inhibitors of kinases downstream of RAS signaling with JAK inhibitors resulted in cell death of cultured cancer cell lines resistant to JAK inhibitors, as did an inhibitor of an antiapoptotic protein. The findings identify a potential therapeutic option for drug-resistant MPNs.

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