title: Targeting the PI3K/Akt pathway in murine MDS/MPN driven by hyperactive Ras.
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.
authors.affiliation: UCSF Benioff Children's Hospital, Department of Pediatrics, University of California, San Francisco, and the Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Akutagawa
authors.affiliation: UCSF Benioff Children's Hospital, Department of Pediatrics, University of California, San Francisco, and the Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.
authors.forename: T Q
authors.initials: TQ
authors.lastname: Huang
authors.affiliation: UCSF Benioff Children's Hospital, Department of Pediatrics, University of California, San Francisco, and the Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.
authors.forename: I
authors.initials: I
authors.lastname: Epstein
authors.affiliation: UCSF Benioff Children's Hospital, Department of Pediatrics, University of California, San Francisco, and the Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Chang
authors.affiliation: UCSF Benioff Children's Hospital, Department of Pediatrics, University of California, San Francisco, and the Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Quirindongo-Crespo
authors.affiliation: UCSF Benioff Children's Hospital, Department of Pediatrics, University of California, San Francisco, and the Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: Cottonham
authors.affiliation: UCSF Benioff Children's Hospital, Department of Pediatrics, University of California, San Francisco, and the Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Dail
authors.affiliation: Johns Hopkins Drug Discovery Program and Departments of Neurology, Psychiatry, and Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: B S
authors.initials: BS
authors.lastname: Slusher
authors.affiliation: Genentech, Department of Translational Oncology, South San Francisco, CA, USA.
authors.forename: L S
authors.initials: LS
authors.lastname: Friedman
authors.affiliation: Genentech, Department of Translational Oncology, South San Francisco, CA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Sampath
authors.affiliation: UCSF Benioff Children's Hospital, Department of Pediatrics, University of California, San Francisco, and the Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.
authors.forename: B S
authors.initials: BS
authors.lastname: Braun
mesh_terms: D000818:Animals; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage / Q000494:pharmacology*; D007191:Indazoles; D015477:Leukemia, Myelomonocytic, Chronic; D054429:Leukemia, Myelomonocytic, Juvenile; D020935:MAP Kinase Signaling System; D051379:Mice; D009190:Myelodysplastic Syndromes / Q000188:drug therapy / Q000378:metabolism*; D009196:Myeloproliferative Disorders / Q000188:drug therapy / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides; D018631:ras Proteins / Q000235:genetics*
chemical_list: C532162:2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine; D006575:Heterocyclic Compounds, 3-Ring; D007191:Indazoles; C548887:MK 2206; D013449:Sulfonamides; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D018631:ras Proteins