PMID- 22696593
OWN - NLM
STAT- MEDLINE
DCOM- 20121031
LR  - 20211203
IS  - 1460-2180 (Electronic)
IS  - 0143-3334 (Print)
IS  - 0143-3334 (Linking)
VI  - 33
IP  - 9
DP  - 2012 Sep
TI  - Sorafenib enhances the therapeutic efficacy of rapamycin in colorectal cancers 
      harboring oncogenic KRAS and PIK3CA.
PG  - 1782-90
LID - 10.1093/carcin/bgs203 [doi]
AB  - Activation of phosphatidylinositol 3-kinase (PI3K)/Akt signaling is associated 
      with tumorigenesis and metastasis of colorectal cancer (CRC). The mammalian 
      target of rapamycin (mTOR) kinase, a downstream effector of PI3K/Akt signaling, 
      regulates tumorigenesis and metastasis of CRCs, indicating that mTOR inhibition 
      may have therapeutic potential. Notwithstanding, many cancers, including CRC, 
      demonstrate resistance to the antitumorigenic effects of rapamycin. In this 
      study, we show that inhibition of mTORC1 with rapamycin leads to feedback 
      activation of PI3K/Akt and Ras-MAPK signaling, resulting in cell survival and 
      possible contribution to rapamycin resistance. Combination with the multikinase 
      inhibitor, sorafenib, abrogates rapamycin-induced activation of PI3K/Akt and 
      Ras-MAPK signaling pathways. Combination of rapamycin with sorafenib 
      synergistically inhibits proliferation of CRC cells. CRCs harboring coexistent 
      KRAS and PIK3CA mutations are partially sensitive to either rapamycin or 
      sorafenib monotherapy, but highly sensitive to combination treatment with 
      rapamycin and sorafenib. Combination with sorafenib enhances therapeutic efficacy 
      of rapamycin on induction of apoptosis and inhibition of cell-cycle progression, 
      migration and invasion of CRCs. We demonstrate efficacy and safety of concomitant 
      treatment with rapamycin and sorafenib at inhibiting growth of xenografts from 
      CRC cells with coexistent mutations in KRAS and PIK3CA. The efficacy and 
      tolerability of combined treatment with rapamycin and sorafenib provides 
      rationale for use in treating CRC patients, particularly those with tumors 
      harboring coexistent KRAS and PIK3CA mutations.
FAU - Gulhati, Pat
AU  - Gulhati P
AD  - Department of Surgery, University of Kentucky, Lexington, Kentucky, USA.
FAU - Zaytseva, Yekaterina Y
AU  - Zaytseva YY
FAU - Valentino, Joseph D
AU  - Valentino JD
FAU - Stevens, Payton D
AU  - Stevens PD
FAU - Kim, Ji Tae
AU  - Kim JT
FAU - Sasazuki, Takehiko
AU  - Sasazuki T
FAU - Shirasawa, Senji
AU  - Shirasawa S
FAU - Lee, Eun Y
AU  - Lee EY
FAU - Weiss, Heidi L
AU  - Weiss HL
FAU - Dong, Jianli
AU  - Dong J
FAU - Gao, Tianyan
AU  - Gao T
FAU - Evers, B Mark
AU  - Evers BM
LA  - eng
GR  - R01 CA133429/CA/NCI NIH HHS/United States
GR  - T32 CA165990/CA/NCI NIH HHS/United States
GR  - R01CA133429/CA/NCI NIH HHS/United States
GR  - P20CA1530343/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 - 20120613
PL  - England
TA  - Carcinogenesis
JT  - Carcinogenesis
JID - 8008055
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Benzenesulfonates)
RN  - 0 (KRAS protein, human)
RN  - 0 (Multiprotein Complexes)
RN  - 0 (Phenylurea Compounds)
RN  - 0 (Proteins)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Pyridines)
RN  - 25X51I8RD4 (Niacinamide)
RN  - 9ZOQ3TZI87 (Sorafenib)
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 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
RN  - EC 3.6.5.2 (ras Proteins)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Antineoplastic Agents/*administration & dosage
MH  - Apoptosis/drug effects
MH  - Benzenesulfonates/*administration & dosage
MH  - Cell Cycle/drug effects
MH  - Cell Line, Tumor
MH  - Class I Phosphatidylinositol 3-Kinases
MH  - Colorectal Neoplasms/*drug therapy/genetics/pathology
MH  - Drug Synergism
MH  - Humans
MH  - MAP Kinase Signaling System
MH  - Male
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Mice
MH  - Multiprotein Complexes
MH  - *Mutation
MH  - Niacinamide/analogs & derivatives
MH  - Phenylurea Compounds
MH  - Phosphatidylinositol 3-Kinases/*genetics
MH  - Proteins/antagonists & inhibitors
MH  - Proto-Oncogene Proteins/*genetics
MH  - Proto-Oncogene Proteins p21(ras)
MH  - Pyridines/*administration & dosage
MH  - Sirolimus/*administration & dosage
MH  - Sorafenib
MH  - TOR Serine-Threonine Kinases
MH  - ras Proteins/*genetics
PMC - PMC3514899
EDAT- 2012/06/15 06:00
MHDA- 2012/11/01 06:00
PMCR- 2013/09/01
CRDT- 2012/06/15 06:00
PHST- 2012/06/15 06:00 [entrez]
PHST- 2012/06/15 06:00 [pubmed]
PHST- 2012/11/01 06:00 [medline]
PHST- 2013/09/01 00:00 [pmc-release]
AID - bgs203 [pii]
AID - 10.1093/carcin/bgs203 [doi]
PST - ppublish
SO  - Carcinogenesis. 2012 Sep;33(9):1782-90. doi: 10.1093/carcin/bgs203. Epub 2012 Jun 
      13.