Determining sensitivity to rapamycin and its analogues in breast cancer patients

Excerpt

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. …