Targeting the Mammalian Target of Rapamycin (mTOR) in Cancer Therapy: Lessons from Past and Future Perspectives

Abstract

Over the last decade, extensive studies have been made to understand the role played by the mammalian target of rapamycin (mTOR) in cancer. Knowledge in this field has been gained from discoveries in basic research as well as from observations made in patients treated with allosteric mTOR inhibitors such as rapamycin. Despite promising preclinical studies, targeting mTOR in cancer therapy has shown limited clinical benefits so far. However, recent findings have revealed the complexity of the functions of mTOR in cancer and have helped develop new strategies to improve the anticancer efficacy of mTOR inhibitors. In particular, a complex network between mTOR and other signaling pathways has been identified that influences the anticancer efficacy of mTOR inhibitors. In addition, an emerging role of mTOR in the tumor microenvironment has been suggested. In this review, we confront the major findings that have been made in the past, both in experimental settings as well as in clinical trials. We further review the strategies that have been designed to further improve the efficacy of therapies targeting mTOR.

Targeting carbonic anhydrase IX improves the anti-cancer efficacy of mTOR inhibitors

“…The mechanisms responsible for the anti-cancer activity of rapamycin are complex and not restricted to its effect on tumor and endothelial cells [2]. Consistent with this, the antiproliferative effect of rapamycin on cancer cells that we describe here is small and cannot solely account for the anti-cancer activity of rapamycin in our study as well as in patients.…”

“…However, in the course of time, cancers adapt to mTOR inhibition and develop resistance mechanisms that are responsible for the limited efficacy of mTOR inhibitors [2]. To date, most identified resistance mechanisms are the consequence of an abrogation of negative feedback loops following mTORC1 inhibition [21].…”

Glioblastoma, hypoxia and autophagy: a survival-prone ‘ménage-à-trois’

“…42, 103 Indeed, dysregulation of the PI3K/Akt/mTOR signaling pathway is common in human cancers, inducing uncontrolled cell proliferation, which can be targeted by rapamycin analogs. However, even if in GBM, the presence of autophagy inducers such as RAD001 (mTOR inhibitor) allowed TMZ to induce an autophagic death signaling, 104 only few cancers responded to such treatment.…”

Mammalian target of rapamycin inhibitor RAD001 sensitizes endometrial cancer cells to paclitaxel-induced apoptosis via the induction of autophagy

“…The results showed that RAD001 sensitized the cells to paclitaxel, suggesting that using a combination treatment involving RAD001 could reduce the cytotoxic effect of paclitaxel, as it was effective at a lower dose. More importantly, RAD001 only targets malignant cancer cells, with few side effects on normal cells, which makes it an ideal targeted drug in the synergistic therapy for future clinical cancer treatment (35). …”