PMID- 19934303
OWN - NLM
STAT- MEDLINE
DCOM- 20100308
LR  - 20220225
IS  - 1557-3265 (Electronic)
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 15
IP  - 23
DP  - 2009 Dec 1
TI  - Inhibition of mammalian target of rapamycin is required for optimal antitumor 
      effect of HER2 inhibitors against HER2-overexpressing cancer cells.
PG  - 7266-76
LID - 10.1158/1078-0432.CCR-09-1665 [doi]
AB  - PURPOSE: A significant fraction of HER2-overexpressing breast cancers exhibit 
      resistance to the HER2 antibody trastuzumab. Hyperactivity of the 
      phosphatidylinositol 3-kinase (PI3K)/AKT pathway confers trastuzumab resistance, 
      and mammalian target of rapamycin (mTOR) is a major downstream effector of 
      PI3K/AKT. Therefore, we examined whether mTOR inhibitors synergize with 
      trastuzumab. EXPERIMENTAL DESIGN: Immunocompetent mice bearing HER2(+) mammary 
      tumors were treated with trastuzumab, the mTOR inhibitor rapamycin, or the 
      combination. Mice were imaged for tumor cell death using an optical Annexin-V 
      probe and with [(18)F]FDG positron emission tomography. The signaling and growth 
      effects of the mTOR inhibitor RAD001 on HER2(+) cells treated with trastuzumab or 
      lapatinib were evaluated. RESULTS: Treatment of mice with trastuzumab plus 
      rapamycin was more effective than single-agent treatments, inducing complete 
      regression of 26 of 26 tumors. The combination induced tumor cell death 
      (Annexin-V binding) and inhibited FDG uptake. Rapamycin inhibited mTOR and tumor 
      cell proliferation as determined by phosphorylated S6 and Ki-67 
      immunohistochemistry, respectively. In culture, the combination of RAD001 plus 
      trastuzumab inhibited cell growth more effectively than either drug alone. 
      Trastuzumab partially decreased PI3K but not mTOR activity. Knockdown of TSC2 
      resulted in HER2-independent activation of mTOR and dampened the response to 
      trastuzumab and lapatinib. Treatment with the HER2 inhibitor lapatinib decreased 
      phosphorylated S6 and growth in TSC2-expressing cells but not in TSC2-knockdown 
      cells. CONCLUSIONS: Inhibition of PI3K and mTOR are required for the 
      growth-inhibitory effect of HER2 antagonists. These findings collectively support 
      the combined use of trastuzumab and mTOR inhibitors for the treatment of HER2(+) 
      breast cancer.
FAU - Miller, Todd W
AU  - Miller TW
AD  - Department of Medicine, Vanderbilt University, Nashville, Tennessee, USA.
FAU - Forbes, James T
AU  - Forbes JT
FAU - Shah, Chirayu
AU  - Shah C
FAU - Wyatt, Shelby K
AU  - Wyatt SK
FAU - Manning, H Charles
AU  - Manning HC
FAU - Olivares, Maria G
AU  - Olivares MG
FAU - Sanchez, Violeta
AU  - Sanchez V
FAU - Dugger, Teresa C
AU  - Dugger TC
FAU - de Matos Granja, Nara
AU  - de Matos Granja N
FAU - Narasanna, Archana
AU  - Narasanna A
FAU - Cook, Rebecca S
AU  - Cook RS
FAU - Kennedy, J Phillip
AU  - Kennedy JP
FAU - Lindsley, Craig W
AU  - Lindsley CW
FAU - Arteaga, Carlos L
AU  - Arteaga CL
LA  - eng
GR  - R01 CA080195/CA/NCI NIH HHS/United States
GR  - K25 CA127349/CA/NCI NIH HHS/United States
GR  - U24CA126588/CA/NCI NIH HHS/United States
GR  - K25CA127349/CA/NCI NIH HHS/United States
GR  - U24 CA126588/CA/NCI NIH HHS/United States
GR  - P50 CA098131/CA/NCI NIH HHS/United States
GR  - P30 CA068485/CA/NCI NIH HHS/United States
GR  - F32 CA121900/CA/NCI NIH HHS/United States
GR  - F32CA121900/CA/NCI NIH HHS/United States
GR  - R01 CA080195-09/CA/NCI NIH HHS/United States
GR  - T32 EB001628/EB/NIBIB NIH HHS/United States
GR  - P50CA98131/CA/NCI NIH HHS/United States
GR  - P30CA68485/CA/NCI NIH HHS/United States
GR  - T32EB001628/EB/NIBIB NIH HHS/United States
GR  - P50 CA098131-06/CA/NCI NIH HHS/United States
GR  - R01CA80195/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 - 20091124
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 (Antibodies, Monoclonal)
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.10.1 (ERBB2 protein, human)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - P188ANX8CK (Trastuzumab)
SB  - IM
MH  - Animals
MH  - Antibodies, Monoclonal/pharmacology
MH  - Antibodies, Monoclonal, Humanized
MH  - Antineoplastic Agents/*pharmacology
MH  - Breast Neoplasms/*metabolism
MH  - Cell Line, Tumor
MH  - Cell Proliferation
MH  - Drug Resistance, Neoplasm
MH  - Female
MH  - Humans
MH  - Intracellular Signaling Peptides and Proteins/*metabolism
MH  - Mice
MH  - Mice, SCID
MH  - Neoplasms/*metabolism
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Phosphorylation
MH  - Protein Serine-Threonine Kinases/*metabolism
MH  - Receptor, ErbB-2/*metabolism
MH  - TOR Serine-Threonine Kinases
MH  - Trastuzumab
PMC - PMC2787848
MID - NIHMS151083
EDAT- 2009/11/26 06:00
MHDA- 2010/03/10 06:00
PMCR- 2010/12/01
CRDT- 2009/11/26 06:00
PHST- 2009/11/26 06:00 [entrez]
PHST- 2009/11/26 06:00 [pubmed]
PHST- 2010/03/10 06:00 [medline]
PHST- 2010/12/01 00:00 [pmc-release]
AID - 1078-0432.CCR-09-1665 [pii]
AID - 10.1158/1078-0432.CCR-09-1665 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2009 Dec 1;15(23):7266-76. doi: 10.1158/1078-0432.CCR-09-1665. 
      Epub 2009 Nov 24.