PMID- 26965285
OWN - NLM
STAT- MEDLINE
DCOM- 20170829
LR  - 20181113
IS  - 1476-5551 (Electronic)
IS  - 0887-6924 (Print)
IS  - 0887-6924 (Linking)
VI  - 30
IP  - 6
DP  - 2016 Jun
TI  - Targeting the PI3K/Akt pathway in murine MDS/MPN driven by hyperactive Ras.
PG  - 1335-43
LID - 10.1038/leu.2016.14 [doi]
AB  - 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.
FAU - Akutagawa, J
AU  - Akutagawa J
AD  - 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.
FAU - Huang, T Q
AU  - Huang TQ
AD  - 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.
FAU - Epstein, I
AU  - Epstein I
AD  - 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.
FAU - Chang, T
AU  - Chang T
AD  - 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.
FAU - Quirindongo-Crespo, M
AU  - Quirindongo-Crespo M
AD  - 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.
FAU - Cottonham, C L
AU  - Cottonham CL
AD  - 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.
FAU - Dail, M
AU  - Dail M
AD  - 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.
FAU - Slusher, B S
AU  - Slusher BS
AD  - Johns Hopkins Drug Discovery Program and Departments of Neurology, Psychiatry, 
      and Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA.
FAU - Friedman, L S
AU  - Friedman LS
AD  - Genentech, Department of Translational Oncology, South San Francisco, CA, USA.
FAU - Sampath, D
AU  - Sampath D
AD  - Genentech, Department of Translational Oncology, South San Francisco, CA, USA.
FAU - Braun, B S
AU  - Braun BS
AD  - 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.
LA  - eng
GR  - P30 CA082103/CA/NCI NIH HHS/United States
GR  - U54 CA143874/CA/NCI NIH HHS/United States
GR  - T32 HD044331/HD/NICHD NIH HHS/United States
GR  - T32 CA108462/CA/NCI NIH HHS/United States
GR  - T32 CA128583/CA/NCI NIH HHS/United States
GR  - K99 CA157950/CA/NCI NIH HHS/United States
GR  - R01 CA173085/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20160212
PL  - England
TA  - Leukemia
JT  - Leukemia
JID - 8704895
RN  - 0 
      (2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine)
RN  - 0 (Heterocyclic Compounds, 3-Ring)
RN  - 0 (Indazoles)
RN  - 0 (MK 2206)
RN  - 0 (Sulfonamides)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 3.6.5.2 (ras Proteins)
SB  - IM
MH  - Animals
MH  - Heterocyclic Compounds, 3-Ring/administration & dosage/*pharmacology
MH  - Indazoles
MH  - Leukemia, Myelomonocytic, Chronic
MH  - Leukemia, Myelomonocytic, Juvenile
MH  - MAP Kinase Signaling System
MH  - Mice
MH  - Myelodysplastic Syndromes/drug therapy/*metabolism
MH  - Myeloproliferative Disorders/drug therapy/*metabolism
MH  - Phosphatidylinositol 3-Kinases/drug effects/*metabolism
MH  - Proto-Oncogene Proteins c-akt/drug effects/*metabolism
MH  - Signal Transduction/drug effects
MH  - Sulfonamides
MH  - ras Proteins/*genetics
PMC - PMC4889473
MID - NIHMS749204
COIS- Conflict of interest: D. Sampath and L. Friedman are employed by Genentech, Inc.; 
      M. Dail and T. Chang are currently employed by Genentech, Inc., but were not when 
      contributing to this work. GDC-0941 was provided by Genentech, Inc. There are no 
      other relevant disclosures.
EDAT- 2016/03/12 06:00
MHDA- 2017/08/30 06:00
PMCR- 2016/08/12
CRDT- 2016/03/12 06:00
PHST- 2015/09/22 00:00 [received]
PHST- 2015/12/13 00:00 [revised]
PHST- 2016/01/04 00:00 [accepted]
PHST- 2016/03/12 06:00 [entrez]
PHST- 2016/03/12 06:00 [pubmed]
PHST- 2017/08/30 06:00 [medline]
PHST- 2016/08/12 00:00 [pmc-release]
AID - leu201614 [pii]
AID - 10.1038/leu.2016.14 [doi]
PST - ppublish
SO  - Leukemia. 2016 Jun;30(6):1335-43. doi: 10.1038/leu.2016.14. Epub 2016 Feb 12.