Translating the PI3K/mTOR pathway and translational control to radiation therapy
Session type: Parallel sessions
Translation initiation is frequently the rate-limiting step of protein synthesis and the point at which the highly regulated process of mRNA translation becomes uncoupled from control restrictions in human cancers. Although the majority of mRNAs are translated through a cap-dependent mechanism, "oncogenic" mRNAs, those involved in tumor angiogenesis, survival, DNA repair responses and cell cycling, among others, have additional requirements that provide druggable targets.
The mTOR pathway regulates cap-dependent mRNA translation through phosphorylation inactivation of 4E-BPs, and activation of S6K1 and 2 and eIF4GI. mTOR is inhibited by a variety of stress conditions, inhibiting cap-dependent mRNA translation. We previously showed that translation initiation factor eIF4GI is an important effect or of mTOR function. Our research is directed to understanding the mTOR/4E-BP1 and mRNA translation regulation axis in human breast cancers and the design of new therapeutic strategies and small molecule inhibitors for treatment of advanced breast and other cancers based on this research.
We found that high levels of eIF4GI mediate radio-resistance in breast tumors, mTORC1/2 inhibition but not TORC1 inhibition alone prevents growth of advanced breast cancer xenografts and enhances radio-sensitivity. Overexpression of eIF4GI and hyper-activated mTOR in breast cancers is shown to promote selective translation of oncogenic, DNA damage repair and survival mRNA translation. We also show that breast cancer stem cells (CSCs) are particularly dependent on high levels of eIF4GI/mTOR activity for survival, and could be selectively radio-sensitized in culture and in tumours as a result of eIF4GI-silencing or mTORC1/2 inhibition.
These studies demonstrate that targeted inhibition of mTORC1/2 catalytic activity or targeted inhibition of specific translation initiation factors is well tolerated in animal models and synergizes with radiation therapy to prevent radiation induced pro-survival tumour and CSC signals of the PI3K-Akt-mTOR pathway.