PMID- 22872574
OWN - NLM
STAT- MEDLINE
DCOM- 20130503
LR  - 20220317
IS  - 1557-3265 (Electronic)
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 18
IP  - 19
DP  - 2012 Oct 1
TI  - Combined PI3K/mTOR and MEK inhibition provides broad antitumor activity in 
      faithful murine cancer models.
PG  - 5290-303
LID - 10.1158/1078-0432.CCR-12-0563 [doi]
AB  - PURPOSE: Anticancer drug development is inefficient, but genetically engineered 
      murine models (GEMM) and orthotopic, syngeneic transplants (OST) of cancer may 
      offer advantages to in vitro and xenograft systems. EXPERIMENTAL DESIGN: We 
      assessed the activity of 16 treatment regimens in a RAS-driven, 
      Ink4a/Arf-deficient melanoma GEMM. In addition, we tested a subset of treatment 
      regimens in three breast cancer models representing distinct breast cancer 
      subtypes: claudin-low (T11 OST), basal-like (C3-TAg GEMM), and luminal B 
      (MMTV-Neu GEMM). RESULTS: Like human RAS-mutant melanoma, the melanoma GEMM was 
      refractory to chemotherapy and single-agent small molecule therapies. Combined 
      treatment with AZD6244 [mitogen-activated protein-extracellular signal-regulated 
      kinase kinase (MEK) inhibitor] and BEZ235 [dual phosphoinositide-3 kinase 
      (PI3K)/mammalian target of rapamycin (mTOR) inhibitor] was the only treatment 
      regimen to exhibit significant antitumor activity, showed by marked tumor 
      regression and improved survival. Given the surprising activity of the "AZD/BEZ" 
      combination in the melanoma GEMM, we next tested this regimen in the 
      "claudin-low" breast cancer model that shares gene expression features with 
      melanoma. The AZD/BEZ regimen also exhibited significant activity in this model, 
      leading us to testing in even more diverse GEMMs of basal-like and luminal breast 
      cancer. The AZD/BEZ combination was highly active in these distinct breast cancer 
      models, showing equal or greater efficacy compared with any other regimen tested 
      in studies of over 700 tumor-bearing mice. This regimen even exhibited activity 
      in lapatinib-resistant HER2(+) tumors. CONCLUSION: These results show the use of 
      credentialed murine models for large-scale efficacy testing of diverse anticancer 
      regimens and predict that combinations of PI3K/mTOR and MEK inhibitors will show 
      antitumor activity in a wide range of human malignancies.
FAU - Roberts, Patrick J
AU  - Roberts PJ
AD  - Department of Genetics, University of North Carolina School of Medicine, Chapel 
      Hill, NC, USA.
FAU - Usary, Jerry E
AU  - Usary JE
FAU - Darr, David B
AU  - Darr DB
FAU - Dillon, Patrick M
AU  - Dillon PM
FAU - Pfefferle, Adam D
AU  - Pfefferle AD
FAU - Whittle, Martin C
AU  - Whittle MC
FAU - Duncan, James S
AU  - Duncan JS
FAU - Johnson, Soren M
AU  - Johnson SM
FAU - Combest, Austin J
AU  - Combest AJ
FAU - Jin, Jian
AU  - Jin J
FAU - Zamboni, William C
AU  - Zamboni WC
FAU - Johnson, Gary L
AU  - Johnson GL
FAU - Perou, Charles M
AU  - Perou CM
FAU - Sharpless, Norman E
AU  - Sharpless NE
LA  - eng
GR  - R01 GM101141/GM/NIGMS NIH HHS/United States
GR  - U19 MH082441/MH/NIMH NIH HHS/United States
GR  - P50-CA58223-09A1/CA/NCI NIH HHS/United States
GR  - P30 CA016086/CA/NCI NIH HHS/United States
GR  - R01 CA148761/CA/NCI NIH HHS/United States
GR  - R01 CA163896/CA/NCI NIH HHS/United States
GR  - T32 CA071341/CA/NCI NIH HHS/United States
GR  - P01 ES014635/ES/NIEHS NIH HHS/United States
GR  - R01 UO1-CA141576/CA/NCI NIH HHS/United States
GR  - R01 P01-ES014635/ES/NIEHS NIH HHS/United States
GR  - P50 CA058223/CA/NCI NIH HHS/United States
GR  - T32 GM007040/GM/NIGMS NIH HHS/United States
GR  - U01 CA141576/CA/NCI NIH HHS/United States
GR  - R01-CA148761/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 - 20120807
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 (AZD 6244)
RN  - 0 (Benzimidazoles)
RN  - 0 (Imidazoles)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (Quinolines)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.25 (MAP Kinase Kinase Kinases)
RN  - RUJ6Z9Y0DT (dactolisib)
SB  - IM
MH  - Animals
MH  - Antineoplastic Combined Chemotherapy Protocols/administration & dosage
MH  - Benzimidazoles/administration & dosage
MH  - Breast Neoplasms/drug therapy
MH  - Female
MH  - Humans
MH  - Imidazoles/administration & dosage
MH  - MAP Kinase Kinase Kinases/*antagonists & inhibitors/metabolism
MH  - Mammary Neoplasms, Animal/*drug therapy/genetics/pathology
MH  - Melanoma/*drug therapy/genetics/pathology
MH  - Mice
MH  - Neoplasms, Experimental/drug therapy/genetics/pathology
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - *Phosphoinositide-3 Kinase Inhibitors
MH  - Quinolines/administration & dosage
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors/metabolism
PMC - PMC3715399
MID - NIHMS487651
COIS- Disclosure of Potential Conflicts of Interest No potential conflicts of interest 
      were disclosed.
EDAT- 2012/08/09 06:00
MHDA- 2013/05/04 06:00
PMCR- 2013/07/18
CRDT- 2012/08/09 06:00
PHST- 2012/08/09 06:00 [entrez]
PHST- 2012/08/09 06:00 [pubmed]
PHST- 2013/05/04 06:00 [medline]
PHST- 2013/07/18 00:00 [pmc-release]
AID - 1078-0432.CCR-12-0563 [pii]
AID - 10.1158/1078-0432.CCR-12-0563 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2012 Oct 1;18(19):5290-303. doi: 10.1158/1078-0432.CCR-12-0563. 
      Epub 2012 Aug 7.