PMID- 26436951
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20151006
LR  - 20240213
IS  - 2157-9024 (Print)
IS  - 2157-9024 (Electronic)
IS  - 2157-9024 (Linking)
VI  - 4
IP  - 10
DP  - 2015 Oct 5
TI  - PIK3CA mutations can initiate pancreatic tumorigenesis and are targetable with 
      PI3K inhibitors.
PG  - e169
LID - 10.1038/oncsis.2015.28 [doi]
AB  - Aberrations in the phosphoinositide 3-kinase (PI3K) signaling pathway have a key 
      role in the pathogenesis of numerous cancers by altering cell growth, metabolism, 
      proliferation and apoptosis. Interest in targeting the PI3K signaling cascade 
      continues, as new agents are being clinically evaluated. PIK3CA mutations result 
      in a constitutively active PI3K and are present in a subset of pancreatic 
      cancers. Here we examine mutant PIK3CA-mediated pancreatic tumorigenesis and the 
      response of PIK3CA mutant pancreatic cancers to dual PI3K/mammalian target of 
      rapamycin (mTOR) inhibition. Two murine models were generated expressing a 
      constitutively active PI3K within the pancreas. An increase in acinar-to-ductal 
      metaplasia and pancreatic intraepithelial neoplasms (PanINs) was identified. In 
      one model these lesions were detected as early as 10 days of age. Invasive 
      pancreatic ductal adenocarcinoma developed in these mice as early as 20 days of 
      age. These cancers were highly sensitive to treatment with dual PI3K/mTOR 
      inhibition. In the second model, PanINs and invasive cancer develop with a 
      greater latency owing to a lesser degree of PI3K pathway activation in this 
      murine model. In addition to PI3K pathway activation, increased ERK1/2 signaling 
      is common in human pancreatic cancers. Phosphorylation of ERK1/2 was also 
      investigated in these models. Phosphorylation of ERK1/2 is demonstrated in the 
      pre-neoplastic lesions and invasive cancers. This activation of ERK1/2 is 
      diminished with dual PI3K/mTOR inhibition. In summary, PIK3CA mutations can 
      initiate pancreatic tumorigenesis and these cancers are particularly sensitive to 
      dual PI3K/mTOR inhibition. Future studies of PI3K pathway inhibitors for patients 
      with PIK3CA mutant pancreatic cancers are warranted.
FAU - Payne, S N
AU  - Payne SN
AD  - University of Wisconsin Carbone Cancer Center, Madison, WI, USA.
FAU - Maher, M E
AU  - Maher ME
AD  - Division of Hematology and Oncology, Department of Medicine, University of 
      Wisconsin, Madison, WI, USA.
FAU - Tran, N H
AU  - Tran NH
AD  - Division of Hematology and Oncology, Department of Medicine, University of 
      Wisconsin, Madison, WI, USA.
FAU - Van De Hey, D R
AU  - Van De Hey DR
AD  - Division of Hematology and Oncology, Department of Medicine, University of 
      Wisconsin, Madison, WI, USA.
FAU - Foley, T M
AU  - Foley TM
AD  - Division of Hematology and Oncology, Department of Medicine, University of 
      Wisconsin, Madison, WI, USA.
FAU - Yueh, A E
AU  - Yueh AE
AD  - Division of Hematology and Oncology, Department of Medicine, University of 
      Wisconsin, Madison, WI, USA.
FAU - Leystra, A A
AU  - Leystra AA
AD  - Department of Oncology, University of Wisconsin, Madison, WI, USA.
FAU - Pasch, C A
AU  - Pasch CA
AD  - University of Wisconsin Carbone Cancer Center, Madison, WI, USA.
FAU - Jeffrey, J J
AU  - Jeffrey JJ
AD  - University of Wisconsin Carbone Cancer Center, Madison, WI, USA.
FAU - Clipson, L
AU  - Clipson L
AD  - Department of Oncology, University of Wisconsin, Madison, WI, USA.
FAU - Matkowskyj, K A
AU  - Matkowskyj KA
AD  - University of Wisconsin Carbone Cancer Center, Madison, WI, USA.
AD  - Department of Pathology and Laboratory Medicine, University of Wisconsin, 
      Madison, WI, USA.
AD  - William S Middleton Memorial Veterans Hospital, Madison, WI, USA.
FAU - Deming, D A
AU  - Deming DA
AD  - University of Wisconsin Carbone Cancer Center, Madison, WI, USA.
AD  - Division of Hematology and Oncology, Department of Medicine, University of 
      Wisconsin, Madison, WI, USA.
AD  - William S Middleton Memorial Veterans Hospital, Madison, WI, USA.
LA  - eng
GR  - P30 CA014520/CA/NCI NIH HHS/United States
PT  - Journal Article
DEP - 20151005
PL  - United States
TA  - Oncogenesis
JT  - Oncogenesis
JID - 101580004
PMC - PMC4632089
EDAT- 2015/10/06 06:00
MHDA- 2015/10/06 06:01
PMCR- 2015/10/01
CRDT- 2015/10/06 06:00
PHST- 2015/08/13 00:00 [received]
PHST- 2015/08/24 00:00 [accepted]
PHST- 2015/10/06 06:00 [entrez]
PHST- 2015/10/06 06:00 [pubmed]
PHST- 2015/10/06 06:01 [medline]
PHST- 2015/10/01 00:00 [pmc-release]
AID - oncsis201528 [pii]
AID - 10.1038/oncsis.2015.28 [doi]
PST - epublish
SO  - Oncogenesis. 2015 Oct 5;4(10):e169. doi: 10.1038/oncsis.2015.28.