Autophagy in anti-cancer therapy
The conserved cellular program of autophagy regulating protein and organelle turnover is important for cancer cell survival and also plays a role in the resistance to anti-cancer therapy. Autophagy is activated as a survival strategy in response to starvation and many types of stress. Anti-cancer therapy including radio- and chemo-therapy and tyrosine kinase inhibitors (TKI)-based therapy also induce autophagy. The impact of autophagy induction on a cell largely depends on a stimulus and a cell type [1, 2]. Generally, autophagy is believed to limit the cytotoxic effects of many drugs. We have found among 350 anti-cancer drugs about 100 drugs to modulate autophagy including TKIs erlotinib and sunitinib, in a phenotypic screen-based assay . We characterized a novel potent small molecule Vps34 inhibitor that has been developed by Sprint Bioscience and used it to potentiate the cytotoxic effects of each of these drugs in breast cancer cell lines . Together with Sprint Bioscience, we are now establishing the mRNA and protein expression profile of the breast cancer cell lines after inhibition of Vps34 to obtain prominent biomarkers for both the activity and the inhibition of autophagy in tumors. We also study the effects of autophagy inhibition on the tumor microenvironment using co-culture experiments and syngeneic mouse xenograft models.
- Sprint Bioscience, NOVUM, Huddinge
- CBCS - Chemical Biology Consortium, KI and SciLife
- K. Wennerberg, FIMM, Finland.
- The COST European autophagy network.
Inhibition of Vps34 reprograms cold into hot inflamed tumors and improves anti-PD-1/PD-L1 immunotherapy.
Noman MZ, Parpal S, Van Moer K, Xiao M, Yu Y, Viklund J, et al
Sci Adv 2020 May;6(18):eaax7881
Targeting autophagy by small molecule inhibitors of vacuolar protein sorting 34 (Vps34) improves the sensitivity of breast cancer cells to Sunitinib.
Dyczynski M, Yu Y, Otrocka M, Parpal S, Braga T, Henley AB, et al
Cancer Lett. 2018 10;435():32-43