PMID- 25326806
OWN - NLM
STAT- MEDLINE
DCOM- 20150612
LR  - 20220321
IS  - 1423-0380 (Electronic)
IS  - 1010-4283 (Linking)
VI  - 36
IP  - 2
DP  - 2015 Feb
TI  - Combine MEK inhibition with PI3K/mTOR inhibition exert inhibitory tumor growth 
      effect on KRAS and PIK3CA mutation CRC xenografts due to reduced expression of 
      VEGF and matrix metallopeptidase-9.
PG  - 1091-7
LID - 10.1007/s13277-014-2667-5 [doi]
AB  - Although epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) 
      cetuximab are used widely to treat KRAS wild-type metastatic colorectal cancer 
      (mCRC), patients become resistant by various mechanisms, including KRAS, BRAF, 
      and PIK3CA mutations, thereafter relapsing. AZD6244 is a potent, selective, and 
      orally available MEK1/2 inhibitor. In this study, we investigated the mechanisms 
      of AZD6244 alone or with BEZ235, an orally available potent inhibitor of 
      phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR), in 
      a KRAS and PIK3CA mutation CRC xenograft model. HCT116 (KRAS (G13D) , PIK3CA 
      (H1047R) mutant) cells were subcutaneously injected into the nude mice. Mice were 
      randomly assigned to treatment with vehicle, cetuximab, AZD6244, BEZ235, or 
      AZD6244 plus BEZ235, for up to 3 weeks; then, all mice were sacrificed, and tumor 
      tissues were subjected to Western blot analysis and immunohistochemical staining. 
      AZD6244 or BEZ235 slightly inhibit tumor growth of HCT116 xenografts, and the 
      combination treatment markedly enhanced their antitumor effects. However, 
      cetuximab had no effect on tumor growth. Western blot analysis and 
      immunohistochemical staining revealed that treatment with AZD6244 or BEZ235 could 
      significantly reduce the phosphorylation level of ERK1/2 or AKT in HCT116 tumor 
      tissues. More interesting, the antiangiogenic effects were substantially enhanced 
      when the agents were combined which may due to the reduced expression of VEGF and 
      matrix metallopeptidase-9 (MMP-9) in tumor tissues. These results suggest that 
      the combination of a selective MEK inhibitor and a PI3K/mTOR inhibitor was 
      effective in CRC harboring with KRAS and PIK3CA mutations. The mechanisms of 
      synergistic antitumor effects may be due to antiangiogenesis.
FAU - E, Jifu
AU  - E J
AD  - Department of Colorectal Surgery, Changhai Hospital, Second Military Medical 
      University, Changhai Road 168, Shanghai, 200433, China.
FAU - Xing, Junjie
AU  - Xing J
FAU - Gong, Haifeng
AU  - Gong H
FAU - He, Jian
AU  - He J
FAU - Zhang, Wei
AU  - Zhang W
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20141019
PL  - Netherlands
TA  - Tumour Biol
JT  - Tumour biology : the journal of the International Society for Oncodevelopmental 
      Biology and Medicine
JID - 8409922
RN  - 0 (AZD 6244)
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (Benzimidazoles)
RN  - 0 (Imidazoles)
RN  - 0 (KRAS protein, human)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Quinolines)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.137 (Class I Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.1.137 (PIK3CA protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.12.2 (MAP Kinase Kinase 1)
RN  - EC 2.7.12.2 (MAP2K1 protein, human)
RN  - EC 3.4.24.35 (Matrix Metalloproteinase 9)
RN  - EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
RN  - EC 3.6.5.2 (ras Proteins)
RN  - PQX0D8J21J (Cetuximab)
RN  - RUJ6Z9Y0DT (dactolisib)
SB  - IM
MH  - Animals
MH  - Antibodies, Monoclonal, Humanized/administration & dosage
MH  - Benzimidazoles/administration & dosage
MH  - Cetuximab
MH  - Class I Phosphatidylinositol 3-Kinases
MH  - Colorectal Neoplasms/*drug therapy/genetics/pathology
MH  - Drug Resistance, Neoplasm/genetics
MH  - HCT116 Cells
MH  - Humans
MH  - Imidazoles/administration & dosage
MH  - MAP Kinase Kinase 1/antagonists & inhibitors/genetics
MH  - Matrix Metalloproteinase 9/*biosynthesis
MH  - Mice
MH  - Phosphatidylinositol 3-Kinases/*genetics
MH  - Protein Kinase Inhibitors/administration & dosage
MH  - Proto-Oncogene Proteins/*genetics
MH  - Proto-Oncogene Proteins p21(ras)
MH  - Quinolines/administration & dosage
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors/*genetics
MH  - Vascular Endothelial Growth Factor A/*biosynthesis
MH  - Xenograft Model Antitumor Assays
MH  - ras Proteins/*genetics
EDAT- 2014/10/20 06:00
MHDA- 2015/06/13 06:00
CRDT- 2014/10/20 06:00
PHST- 2014/09/02 00:00 [received]
PHST- 2014/09/19 00:00 [accepted]
PHST- 2014/10/20 06:00 [entrez]
PHST- 2014/10/20 06:00 [pubmed]
PHST- 2015/06/13 06:00 [medline]
AID - 10.1007/s13277-014-2667-5 [doi]
PST - ppublish
SO  - Tumour Biol. 2015 Feb;36(2):1091-7. doi: 10.1007/s13277-014-2667-5. Epub 2014 Oct 
      19.