Targeting the PI3K/Akt pathway in murine MDS/MPN driven by hyperactive Ras

J. Akutagawa, T. Q. Huang, I. Epstein, T. Chang, M. Quirindongo-Crespo, C. L. Cottonham, M. Dail, B. S. Slusher, L. S. Friedman, D. Sampath, B. S. Braun

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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, Kras D12 and Mx1-Cre, Nf1 flox/- mice accurately model many aspects of CMML and JMML. Treating Mx1-Cre, Kras D12 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 .

Original languageEnglish (US)
Pages (from-to)1335-1343
Number of pages9
JournalLeukemia
Volume30
Issue number6
DOIs
StatePublished - Jun 1 2016

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ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Akutagawa, J., Huang, T. Q., Epstein, I., Chang, T., Quirindongo-Crespo, M., Cottonham, C. L., Dail, M., Slusher, B. S., Friedman, L. S., Sampath, D., & Braun, B. S. (2016). Targeting the PI3K/Akt pathway in murine MDS/MPN driven by hyperactive Ras. Leukemia, 30(6), 1335-1343. https://doi.org/10.1038/leu.2016.14