Targeting mLST8 in mTORC2-dependent cancers
Kim, Laura Chonghae
The mTOR kinase acts in two distinct complexes, mTORC1 and mTORC2, that sense environmental cues and coordinate downstream cellular processes. mTOR signaling is aberrantly regulated in many diseases including cancer. The work described in this dissertation focuses on role of mTORC2 as a promoter of cancer cell proliferation and as a target to inhibit tumor growth. Amplification of RICTOR, an mTORC2 co-factor, was recently identified as an alteration in several cancer subtypes that sensitizes tumors to mTOR kinase inhibition, suggesting upregulation of Rictor alone could activate the mTOR signaling node. We determined that increased expression of Rictor promotes formation of mTORC2 at the expense of mTORC1, leading to increased proliferation of cancer cells. This work also suggests tumors harboring amplification of RICTOR could benefit from mTORC2-specific inhibition. Although small molecule inhibitors of mTORC2 are not yet available, we have identified mLST8, traditionally considered a shared component of both mTOR complexes, to be selectively required for mTORC2 function. We show that mLST8 acts as a molecular bridge between the mTOR kinase and mTORC2 regulatory co-factor Sin1 to maintain mTORC2 integrity. Furthermore, loss of mLST8 in RICTOR-amplified non-small cell lung cancer or PTEN-null prostate cancer cells dramatically reduced tumor growth in xenograft models, suggesting that targeting mLST8 may be a viable strategy for inhibition of mTORC2 in the treatment of mTORC2-dependent cancers.