A Brief Note On The Mammalian Target Of Rapamycin ( Mtor )
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mTOR inhibition in breast cancer.
What is already known;
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase and downstream member of the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) and adenosine monophosphate-activated protein kinase (AMPK) pathways, with an essential role in cell growth, survival, and autophagy. mTOR is a component of two structurally similar complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), which are however functionally distinct; mTORC1 promotes mRNA translation and protein synthesis by phosphorylation of ribosomal protein S6 kinase (S6K1) and eIF4E binding protein 1 (4E-BP1), and inhibits autophagy. mTORC2 organizes the cellular actin cytoskeleton and regulates AKT…show more content… The luminal A subtype of breast cancer had the highest frequency of PIK3CA mutation (45%), and the basal subtype had the lowest (9%). Additional identified aberrations resulting in the dysregulation of the PI3K/mTOR pathway include Akt and PTEN mutations, or loss of PTEN protein [11,12].
The concept of mTOR inhibition in breast cancer was firstly supported by preclinical evidence demonstrating activation of the PI3K/mTOR pathway after long-term estrogen deprivation [13,14]; estrogen-deprived cells relied heavily on the PI3K signaling pathway, making this an important mechanism of acquired endocrine resistance. Combined use of anti-estrogens (tamoxifen/ letrosole) with rapamycin analogues demonstrated increased anti-tumour activity and reversal of endocrine resistance secondary to PI3K/mTOR activation in preclinical models [15-18].
In the metastatic setting, clinical trials using single agent mTOR inhibitors (everolimus/ temsirolimus) demonstrated modest activity with a response rate ranging between 9-12% [19-20]. In an effort to enrich for PIK3CA mutations, a clinical trial of temsirolimus alone in hormone receptor positive or HER-2 positive metastatic breast cancer patients, failed to demonstrate higher activity. PIK3CA mutations were not associated with a higher response rate, however it was the primary tumours that were analysed, and not the recurrent or metastatic sites, which may have obscured