Abstract
Mammalian target of rapamycin (mTOR) is a kinase with sequence homology to phosphoinositol-3 kinase (PI3K). It is a downstream mediator in the PI3K/AKT pathway, which regulates proliferation, survival, mobility and angiogenesis. The targets of mTOR include p70s6 kinase and 4E-BP1 (for review, see Bjornsti and Houghton [1]). Rapamycin is an antibiotic and fungicide isolated from Streptomyces hygroscopicus that inhibits mTOR activity and has been approved as an immunosuppressive drug in organ transplant patients. Interest in rapamycin and analogues as cancer treatments is growing [2] because of the observation that the PI3K/AKT pathway is often altered in cancers. This can occur via mutation in the tumour suppressor gene PTEN, which downregulates the pathway, or over-expression of receptors (such as HER2) that stimulate the pathway. It can also occur via over-expression of other proteins in the pathway (such as AKT/protein kinase B) due to gene amplification or failure to break down the proteins. Rapamycin itself has poor aqueous solubility and is not stable, and so several analogues (CCI-779, RAD001 and AP23573) have been developed that are being tested in clinical trials for cancer treatment. These new drugs can potentially be used for the treatment of breast cancer once those patients who will respond to the drug can be identified. In this review I summarize two recent papers that provide insight into the determinants of sensitivity to rapamycin and the potential synergism with conventional chemotherapies.
Highlights
Mammalian target of rapamycin is a kinase with sequence homology to phosphoinositol-3 kinase (PI3K). It is a downstream mediator in the PI3K/AKT pathway, which regulates proliferation, survival, mobility and angiogenesis
Interest in rapamycin and analogues as cancer treatments is growing [2] because of the observation that the PI3K/AKT pathway is often altered in cancers
This can occur via mutation in the tumour suppressor gene PTEN, which downregulates the pathway, or over-expression of receptors that stimulate the pathway
Summary
Mammalian target of rapamycin (mTOR) is a kinase with sequence homology to phosphoinositol-3 kinase (PI3K). Study of breast cancer cell lines has suggested that cells that express the active (phosphorylated) form of AKT are sensitive to rapamycin treatment [3], as are those that are oestrogen receptor (ER) positive, lack PTEN, or overexpress HER2 [4]. Zhou and coworkers [5] examined 165 primary breast cancers with antibodies directed against HER2 and phosphorylated forms of AKT, mTOR and 4E-BP1 (a downstream target of mTOR) They compared staining in the primary breast tumours with that seen in normal breast epithelium, fibroadenoma, intraductal hyperplasia and ductal carcinoma in situ. Further work in this field is required to determine which target(s) are most useful for determining sensitivity and whether IHC is the best method to detect them
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