PMID- 21115425
OWN - NLM
STAT- MEDLINE
DCOM- 20110802
LR  - 20211203
IS  - 1938-0666 (Electronic)
IS  - 1526-8209 (Linking)
VI  - 10 Suppl 3
DP  - 2010 Nov
TI  - Evolving strategies for overcoming resistance to HER2-directed therapy: targeting 
      the PI3K/Akt/mTOR pathway.
PG  - S72-8
LID - 10.3816/CBC.2010.s.015 [doi]
AB  - Human epidermal growth factor receptor 2-positive (HER2+) breast cancers, which 
      account for 25%-30% of breast cancers, are characterized by an aggressive course 
      and a high propensity for recurrence in the 4 years following diagnosis. The use 
      of trastuzumab-based chemotherapy in the adjuvant setting has markedly improved 
      the outcome for patients with early stage HER2+ breast cancer. Likewise the use 
      of trastuzumab in combination with chemotherapy in patients with metastatic HER2+ 
      breast cancers has prolonged survival, with current expected median survival of 
      about 3 years. Despite these major improvements in outcome, approximately 10% of 
      patients develop a distant recurrence following adjuvant trastuzumab-based 
      chemotherapy, and all patients with metastatic disease eventually develop disease 
      progression. Known mechanisms of resistance to trastuzumab include increased 
      signaling through upstream growth factors, phosphatase and tensin (PTEN) 
      deficiency and alterations of the HER2 receptor. Many of these mechanisms are 
      being targeted in the clinic in an attempt to improve outcome for patients with 
      HER2+ breast cancers. The phosphatidylinositol 3-kinase (PI3K) pathway plays a 
      key role in trastuzumab-resistance, through these and other mechanisms, and 
      represents a logical target for drug development for trastuzumab-resistant breast 
      cancers. The use of mammalian target of rapamycin (mTOR) inhibition has been 
      demonstrated to potentially reverse resistance to trastuzumab in patients with 
      HER2+, metastatic breast cancers. Phase I and II trials have produced encouraging 
      results when the mTOR inhibitor, everolimus, was combined with trastuzumab with 
      or without chemotherapy, in patients with trastuzumab-resistant HER2+ metastatic 
      breast cancer. These results are being confirmed in ongoing phase III trials in 
      the first-line and trastuzumab-resistant settings. The mechanism of how mTOR 
      inhibitors reverse resistance to trastuzumab remains largely unexplained. Other 
      agents targeting the PI3K pathway in trastuzumab-resistant breast cancers are in 
      early phase clinical trials.
FAU - Nahta, Rita
AU  - Nahta R
AD  - Department of Pharmacology, Emory University,Winship Cancer Institute, 1365 
      Clifton Road, Atlanta, GA 30322, USA.
FAU - O'Regan, Ruth M
AU  - O'Regan RM
LA  - eng
PT  - Journal Article
PT  - Review
PL  - United States
TA  - Clin Breast Cancer
JT  - Clinical breast cancer
JID - 100898731
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.137 (Phosphatidylinositol 3-Kinase)
RN  - EC 2.7.10.1 (ERBB2 protein, human)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - P188ANX8CK (Trastuzumab)
SB  - IM
MH  - Antibodies, Monoclonal/therapeutic use
MH  - Antibodies, Monoclonal, Humanized
MH  - Antineoplastic Agents/therapeutic use
MH  - Breast Neoplasms/*drug therapy/enzymology
MH  - Clinical Trials, Phase I as Topic
MH  - Clinical Trials, Phase II as Topic
MH  - Drug Resistance, Neoplasm/*drug effects
MH  - Female
MH  - Humans
MH  - Molecular Targeted Therapy/methods
MH  - Neoplasm Proteins/*antagonists & inhibitors/physiology
MH  - Phosphatidylinositol 3-Kinase/metabolism
MH  - *Phosphoinositide-3 Kinase Inhibitors
MH  - Proto-Oncogene Proteins c-akt/*antagonists & inhibitors/metabolism
MH  - Receptor, ErbB-2/drug effects
MH  - Signal Transduction/drug effects
MH  - TOR Serine-Threonine Kinases/*antagonists & inhibitors/metabolism
MH  - Trastuzumab
EDAT- 2010/12/01 06:00
MHDA- 2011/08/04 06:00
CRDT- 2010/12/01 06:00
PHST- 2010/12/01 06:00 [entrez]
PHST- 2010/12/01 06:00 [pubmed]
PHST- 2011/08/04 06:00 [medline]
AID - D064347V6516801Q [pii]
AID - 10.3816/CBC.2010.s.015 [doi]
PST - ppublish
SO  - Clin Breast Cancer. 2010 Nov;10 Suppl 3:S72-8. doi: 10.3816/CBC.2010.s.015.