Therapeutic targets: MTOR and related pathways

Abstract

The mammalian target of rapamycin (mTOR), a protein kinase of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, has a central role in controlling malignant cellular growth. As a result, mTOR is viewed as an important target for anticancer drug development. Inhibitors of mTOR currently under evaluation in cancer clinical trials are rapamycin (also known as sirolimus, Wyeth) and derivatives temsirolimus (CCI-779, Wyeth), everolimus, (RAD001, Novartis Pharma AG), and AP23573 (Ariad Pharmaceuticals). Preclinical studies suggest that sensitivity to mTOR inhibitors may correlate with activation of the PI3K pathway and/or with aberrant expression of cell cycle regulatory or anti-apoptotic proteins. Clinical trial results show that mTOR inhibitors are well tolerated and may induce prolonged stable disease and tumor regressions in cancer patients. Future research should evaluate optimal, schedule, patient selection, and combination strategies for this novel class of agents.

PIK3CA and PTEN mutations in adenoid cystic carcinoma of the breast metastatic to kidney

“…PTEN and PIK3CA are two important tumor suppressor genes and oncogenes in the mammalian target of rapamycin (mTOR) signaling pathway. 5 MTOR is a protein kinase that has a central role in controlling cancer growth and progression. It integrates signals from growth factors, energy stores and hypoxia.…”

“…It integrates signals from growth factors, energy stores and hypoxia. 5 Phosphoinositide kinase (PIK) is a lipid kinase that phosphorylates the inositol ring of phosphoinositides, acting as signal transducers. Mutational activation of PIK3CA is essential for carcinogenesis in some cancers.…”

“…Activation of class IA proteins might activate several signaling pathways including AKT and Rictor-mTOR complex. 5,11 PI3-AKT signals govern several transcription factors including forkhead box (FOXO) proteins and nuclear factor κB (NFκB). 13 NFκB acts as a positive regulator of cell survival, proliferation, cellular invasion and angiogenesis.…”

“…Also, three rapamycin analogs, temsirolimus (CCI-779, Wyeth), everolimus (RAD001, Novartis Pharma AG) and AP23573 (Ariad Pharmaceuticals) have been included in clinical trials for the treatment of cancer. 5 To date, clinical trials results showed that mTOR inhibitors were well tolerated and might induce prolonged stable disease and tumor regressions in cancer patients. 5 Other components of this vital signaling pathway might also become the potential targets for specific small molecules.…”

“…Both PIK3CA and PTEN are integral part of the mammalian target of rapamycin (mTOR) signaling pathway. 5 MTOR, a protein kinase of the PIK3/Akt signaling pathway, plays a central role in controlling malignant growth, cell cycle progression and proliferation. 5 …”