克拉斯
PI3K/AKT/mTOR通路
神经母细胞瘤RAS病毒癌基因同源物
蛋白激酶B
癌症研究
幼年粒单核细胞白血病
MAPK/ERK通路
MEK抑制剂
PTPN11型
骨髓增生异常综合症
髓样
医学
曲美替尼
生物
免疫学
内科学
信号转导
造血
癌症
骨髓
干细胞
细胞生物学
结直肠癌
作者
Jon Akutagawa,Teng Huang,Inbal Epstein,Tiffany Chang,Maricel Quirindongo-Crespo,Charisa Cottonham,Monique Dail,Barbara S. Slusher,Lori S. Friedman,Deepak Sampath,Benjamin S. Braun
出处
期刊:Leukemia
[Springer Nature]
日期:2016-02-12
卷期号:30 (6): 1335-1343
被引量:35
摘要
Chronic and juvenile myelomonocytic leukemias (CMML and JMML) are myelodysplastic/myeloproliferative neoplasia (MDS/MPN) overlap syndromes that respond poorly to conventional treatments. Aberrant Ras activation because of NRAS, KRAS, PTPN11, CBL and NF1 mutations is common in CMML and JMML. However, no mechanism-based treatments currently exist for cancers with any of these mutations. An alternative therapeutic strategy involves targeting Ras-regulated effector pathways that are aberrantly activated in CMML and JMML, which include the Raf/MEK/ERK and phosphoinositide-3′-OH kinase (PI3K)/Akt cascades. Mx1-Cre, KrasD12 and Mx1-Cre, Nf1flox/− mice accurately model many aspects of CMML and JMML. Treating Mx1-Cre, KrasD12 mice with GDC-0941 (also referred to as pictilisib), an orally bioavailable inhibitor of class I PI3K isoforms, reduced leukocytosis, anemia and splenomegaly while extending survival. However, GDC-0941 treatment attenuated activation of both PI3K/Akt and Raf/MEK/ERK pathways in primary hematopoietic cells, suggesting it could be acting through suppression of Raf/MEK/ERK signals. To interrogate the importance of the PI3K/Akt pathway specifically, we treated mice with the allosteric Akt inhibitor MK-2206. This compound had no effect on Raf/MEK/ERK signaling, yet it also induced robust hematologic responses in Kras and Nf1 mice with MPN. These data support investigating PI3K/Akt pathway inhibitors as a therapeutic strategy in JMML and CMML patients.
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