Figure 4.

Autophagy promotes cancer drug resistance. (A) Autophagy is induced in tumors by many different cancer therapeutic approaches, including irradiation, inhibition of PI3K, AKT or mTOR, as well as other conventional and targeted therapies. As a result of autophagy induction, tumor cells are more resistant to apoptosis, with an interesting mechanism revealed recently showing targeted turnover of FOXO3A by autophagy to prevent FOXO3A-dependent induction of Puma, a BH3-only pro-apoptotic protein [119]. Autophagy may also promote drug resistance by promoting selection for a CSC phenotype, as has been suggested by work in breast cancer [117] and glioblastoma [118]. (B) CQ and its derivatives are the mainstay of efforts to inhibit autophagy in a clinical setting and this has seen some efficacy in combination with conventional therapies for some cancers and drug combinations. Clinical trials with the combination of CQ and mTOR inhibitors are ongoing and there is particular interest in testing DQ661, which has the dual activity of inhibiting autophagy and mTOR at the lysosome. New generation autophagy inhibitors include small molecules targeted at catalytic components of autophagosome biogenesis, including ULK1, VPS34 and ATG4B.