Rheb/mTOR activation and regulation in cancer: novel treatment strategies beyond rapamycin

Abstract

mTOR exists in two distinct complexes. mTOR complex 1 (mTORC1) is potently inhibited by the immunosupressive macrolide rapamycin; whereas, mTORC2 is insensitive to this durg. These mTOR complexes play an integral role in the regulation of many cellular processes including protein synthesis, autophagy, lipid synthesis, mitochondrial metabolism/biogenesis, and cell cycle. Both mTOR complexes are important for maintaining cellular homeostasis and the growth of many types of cancer. Rapamycin and rapalogs have been effective in treating only a small number of these cancers, and other methods are being developed in order to address the short-comings of these drugs. The most direct of these approaches include ATP-competitive inhibitors of the mTOR kinase or dual inhibitors of both mTOR and PI3 kinase. However, other methods of inhibiting mTORC1 may prove clinically useful as well. These include amino acid depletion using asparaginase and inhibition of the Rheb GTPases with farnesyl transferase inhibitors or statins. Most excitingly, mTORC1 activation has been shown to cause and sensitize cells to DNA damage and ER stress. Many of the drugs currently used in the clinic for the treatment of cancer cause these types of stress, and existing drugs may be tailored to treat tumors with high mTORC1 activity.