Abstract
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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Acknowledgements
This work was supported by the NF Preclinical Consortium and NF Therapeutic Consortium of the Children's Tumor Foundation, and by the National Cancer Institute Cancer Center Support Grant P30CA082103. BSB was a St Baldrick’s Foundation Scholar and received support for this work from NIH awards U54CA143874 and R01CA173085, an ASH Bridge Grant from the American Society of Hematology and the Frank A Campini Foundation. TQH was supported by NIH training grants T32CA128583 and T32HD044331 and CLC was supported by T32CA108462. TC is a St Baldrick’s Foundation Fellow. MD was supported by grants from the William Lawrence and Blanche Hughes Foundation and NIH award K99CA157950.
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DS and LF are employed by Genentech; MD and TC are currently employed by Genentech, but were not when contributing to this work.
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Akutagawa, J., Huang, T., Epstein, I. et al. Targeting the PI3K/Akt pathway in murine MDS/MPN driven by hyperactive Ras. Leukemia 30, 1335–1343 (2016). https://doi.org/10.1038/leu.2016.14
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DOI: https://doi.org/10.1038/leu.2016.14
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