mTOR Inhibitors in Advanced Biliary Tract Cancers

Abstract

Patients with advanced biliary tract cancers (BTCs), including cholangiocarcinoma (CCA), have poor prognosis so novel treatment is warranted for advanced BTC. In current review, we discuss the limitations of current treatment in BTC, the importance of mTOR signalling in BTC, and the possible role of mTOR inhibitors as a future treatment in BTC. Chemotherapy with gemcitabine-based chemotherapy is still the standard of care and no targeted therapy has been established in advanced BTC. PI3K/AKT/mTOR signaling pathway linking to several other pathways and networks regulates cancer proliferation and progression. Emerging evidences reveal mTOR activation is associated with tumorigenesis and drug-resistance in BTC. Rapalogs, such as sirolimus and everolimus, partially inhibit mTOR complex 1 (mTORC1) and exhibit anti-cancer activity in vitro and in vivo in BTC. Rapalogs in clinical trials demonstrate some activity in patients with advanced BTC. New-generation mTOR inhibitors against ATP-binding pocket inhibit both TORC1 and TORC2 and demonstrate more potent anti-tumor effects in vitro and in vivo, however, prospective clinical trials are warranted to prove its efficacy in patients with advanced BTC.

Keywords: advanced biliary tract cancers; mTOR.

Figure 1

The signaling transduction of mTOR pathway. Extracellular signals such as growth factors and cytokines binding to the receptors stimulate RAS/RAF/MEK/ERK and PI3K/AKT/mTOR caspases. mTOR exists in two functionally and structurally distinct complexes, mTORC1 and mTORC2. Both mTORC1/2 contain different core components so they phosphorylate a distinct set of substrates and exhibit distinct function. PTEN is a negative regulator for PI3K/AKT. In addition, ERK/RSK, AMPK, and p53 regulate mTORC1 through TSC2 regulation. Rapalogs mainly inhibit mTORC1 and new-generation mTOR inhibitors such as MLN0128 inhibitor both mTORC1/2. Blue t-bar indicates inhibition, blue arrow indicates stimulation/activation, red t-bar indicates inhibition by drugs, and dashed square indicates mTOR1/2 complexes.