Can mTOR kinase inhibitors beat rapalogues in fighting against cancer?
Posted: 19 February 2014 | Shi-Yong Sun (Emory University School of Medicine and Winship Cancer Institute) | No comments yet
The mammalian target of rapamycin (mTOR) has emerged as a promising cancer therapeutic target. Some rapamycin analogues (rapalogues) as mTOR allosteric inhibitors are FDA-approved drugs for treatment of certain types of cancers. However, the modest clinical anticancer activity of rapalogues, which preferentially inhibit mTOR complex 1, in most types of cancer, has spurred the development of ATP competitive mTOR kinase inhibitors (TORKinibs) that inhibit both mTOR complex 1 and complex 2, in the hope of developing a novel generation of mTOR inhibitors with better therapeutic efficacy than rapalogues. So far, several TORKinibs have been developed and some are under clinical testing. With a strong rationale, we expect great success in the treatment of cancer with TORKinibs.
Mammalian target of rapamycin (mTOR) is a serine-threonine kinase that belongs to the phosphatidylinositol 3-kinase (PI3K)-related kinase (PIKK) family and plays a central role in positively regulating cell growth, survival and other cellular functions. It is generally thought that mTOR exerts these biological functions through interacting with multiple proteins and forming two distinct complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). mTORC1, which is composed of mTOR and other four associated proteins, raptor, mLST8, PRAS40 and DEPTOR, controls cell growth primarily by enhancing translation of multiple oncogenic proteins such as cyclin D1, c-Myc, hypoxia-inducible factor 1 (HIF1) and vascular endothelial growth factor (VEGF) through activating S6 kinase (S6K) and suppressing eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1). mTORC2, which contains mTOR, rictor, mLST8, DEPTOR, mSin1 and protor, positively regulates cell survival and proliferation primarily by phosphorylating Akt and other proteins such as serum and glucocorticoid-inducible kinase (SGK) and PKCα1-4. Hence both mTORC1 and mTORC2 are involved in the positive regulation of cancer cell survival and proliferation. Due to a hyperactive mTOR axis in many types of human cancers, mTOR and mTORCs have emerged as promising cancer therapeutic targets3,5,6.