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RAS signaling promotes resistance to JAK inhibitors by suppressing BAD-mediated apoptosis.
Sci Signal 2014; 7(357):ra122SS

Abstract

Myeloproliferative neoplasms (MPNs) frequently have an activating mutation in the gene encoding Janus kinase 2 (JAK2). Thus, targeting the pathway mediated by JAK and its downstream substrate, signal transducer and activator of transcription (STAT), may yield clinical benefit for patients with MPNs containing the JAK2(V617F) mutation. Although JAK inhibitor therapy reduces splenomegaly and improves systemic symptoms in patients, this treatment does not appreciably reduce the number of neoplastic cells. To identify potential mechanisms underlying this inherent resistance phenomenon, we performed pathway-centric, gain-of-function screens in JAK2(V617F) hematopoietic cells and found that the activation of the guanosine triphosphatase (GTPase) RAS or its effector pathways [mediated by the kinases AKT and ERK (extracellular signal-regulated kinase)] renders cells insensitive to JAK inhibition. Resistant MPN cells became sensitized to JAK inhibitors when also exposed to inhibitors of the AKT or ERK pathways. Mechanistically, in JAK2(V617F) cells, a JAK2-mediated inactivating phosphorylation of the proapoptotic protein BAD [B cell lymphoma 2 (BCL-2)-associated death promoter] promoted cell survival. In sensitive cells, exposure to a JAK inhibitor resulted in dephosphorylation of BAD, enabling BAD to bind and sequester the prosurvival protein BCL-XL (BCL-2-like 1), thereby triggering apoptosis. In resistant cells, RAS effector pathways maintained BAD phosphorylation in the presence of JAK inhibitors, yielding a specific dependence on BCL-XL for survival. In patients with MPNs, activating mutations in RAS co-occur with the JAK2(V617F) mutation in the malignant cells, suggesting that RAS effector pathways likely play an important role in clinically observed resistance.

Authors+Show Affiliations

Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA.Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Harvard Medical School, Boston, MA 02115, USA.Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA.MLL Munich Leukemia Laboratory, Max-Lebsche-Platz 31, 81377 Munich, Germany.MLL Munich Leukemia Laboratory, Max-Lebsche-Platz 31, 81377 Munich, Germany.Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Harvard Medical School, Boston, MA 02115, USA.Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA. kris.wood@duke.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25538080

Citation

Winter, Peter S., et al. "RAS Signaling Promotes Resistance to JAK Inhibitors By Suppressing BAD-mediated Apoptosis." Science Signaling, vol. 7, no. 357, 2014, pp. ra122.
Winter PS, Sarosiek KA, Lin KH, et al. RAS signaling promotes resistance to JAK inhibitors by suppressing BAD-mediated apoptosis. Sci Signal. 2014;7(357):ra122.
Winter, P. S., Sarosiek, K. A., Lin, K. H., Meggendorfer, M., Schnittger, S., Letai, A., & Wood, K. C. (2014). RAS signaling promotes resistance to JAK inhibitors by suppressing BAD-mediated apoptosis. Science Signaling, 7(357), pp. ra122. doi:10.1126/scisignal.2005301.
Winter PS, et al. RAS Signaling Promotes Resistance to JAK Inhibitors By Suppressing BAD-mediated Apoptosis. Sci Signal. 2014 Dec 23;7(357):ra122. PubMed PMID: 25538080.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - RAS signaling promotes resistance to JAK inhibitors by suppressing BAD-mediated apoptosis. AU - Winter,Peter S, AU - Sarosiek,Kristopher A, AU - Lin,Kevin H, AU - Meggendorfer,Manja, AU - Schnittger,Susanne, AU - Letai,Anthony, AU - Wood,Kris C, Y1 - 2014/12/23/ PY - 2014/12/25/entrez PY - 2014/12/30/pubmed PY - 2015/9/1/medline SP - ra122 EP - ra122 JF - Science signaling JO - Sci Signal VL - 7 IS - 357 N2 - Myeloproliferative neoplasms (MPNs) frequently have an activating mutation in the gene encoding Janus kinase 2 (JAK2). Thus, targeting the pathway mediated by JAK and its downstream substrate, signal transducer and activator of transcription (STAT), may yield clinical benefit for patients with MPNs containing the JAK2(V617F) mutation. Although JAK inhibitor therapy reduces splenomegaly and improves systemic symptoms in patients, this treatment does not appreciably reduce the number of neoplastic cells. To identify potential mechanisms underlying this inherent resistance phenomenon, we performed pathway-centric, gain-of-function screens in JAK2(V617F) hematopoietic cells and found that the activation of the guanosine triphosphatase (GTPase) RAS or its effector pathways [mediated by the kinases AKT and ERK (extracellular signal-regulated kinase)] renders cells insensitive to JAK inhibition. Resistant MPN cells became sensitized to JAK inhibitors when also exposed to inhibitors of the AKT or ERK pathways. Mechanistically, in JAK2(V617F) cells, a JAK2-mediated inactivating phosphorylation of the proapoptotic protein BAD [B cell lymphoma 2 (BCL-2)-associated death promoter] promoted cell survival. In sensitive cells, exposure to a JAK inhibitor resulted in dephosphorylation of BAD, enabling BAD to bind and sequester the prosurvival protein BCL-XL (BCL-2-like 1), thereby triggering apoptosis. In resistant cells, RAS effector pathways maintained BAD phosphorylation in the presence of JAK inhibitors, yielding a specific dependence on BCL-XL for survival. In patients with MPNs, activating mutations in RAS co-occur with the JAK2(V617F) mutation in the malignant cells, suggesting that RAS effector pathways likely play an important role in clinically observed resistance. SN - 1937-9145 UR - https://www.unboundmedicine.com/medline/citation/25538080/RAS_signaling_promotes_resistance_to_JAK_inhibitors_by_suppressing_BAD_mediated_apoptosis_ L2 - http://stke.sciencemag.org/cgi/pmidlookup?view=long&pmid=25538080 DB - PRIME DP - Unbound Medicine ER -