Therapeutic potential of mTOR inhibitors for targeting cancer stem cells

Abstract

The mammalian target of rapamycin (mTOR) pathway is aberrantly activated in many cancer types. As the intricate network of regulatory mechanisms controlling mTOR activity is uncovered, more refined drugs are designed and tested in clinical trials. While first generation mTOR inhibitors have failed to show clinical efficacy due partly to the feedback relief of oncogenetic circuits, newly developed inhibitors show greater promise as anti-cancer agents. An effective drug must defeat the cancer stem cells (CSCs) while sparing the normal stem cells. Due to its opposing role on normal and malignant stem cells, mTOR lends itself very well as a therapeutic target. Indeed, a preferential inhibitory effect on CSCs has already been shown for some mTOR inhibitors. These results provide a compelling rationale for the clinical development of mTOR-targeted therapies.

Keywords: cancer stem cells, drug resistance; mTOR; personalized medicine; tumour heterogeneity.

Figure 1

Schematic view of cancer stem cell (CSC) evolution during the course of the disease. A) Intra‐tumour heterogeneity can arise from intrinsic differences between CSCs and their progeny or from clonal evolution. In the CSC model, only the CSCs have the ability to generate a tumour. In the clonal evolution model, every cell within a tumour has similar tumourigenic potential. The CSC hierarchical model suggests that CSCs are the only relevant target for therapy. In contrast, the clonal evolution model suggests that all tumour cells must be targeted, as all are equally able of causing relapse after therapy. B) While traditional therapy may initially control disease by effectively debulking tumours, the tumours invariably recur due to the ability of CSCs to survive and repopulate the tumour mass. However, the CSC model and the clonal evolution model are not mutually exclusive, and clonal evolution can happen in CSCs, leading to the acquisition of new tumour cell properties. CSC‐targeted therapy renders tumours unable to maintain themselves or grow. However, resistant clones can emerge under the selective pressures of targeted therapy, leading to the emergence of a tumour with new characteristics