Department of Surgery & Cancer, Imperial College London
Doi
Abstract
The major obstacle to effective breast cancer (BC) treatment has been the development of drug resistance, and there is an urgent need to develop treatments able to target resistant cancers. The tumour suppressive transcription factor FOXO3 promotes cell cycle arrest, senescence and cell death, and is often down-regulated as an adaptive response in cancer and particularly in chemotherapeutic drug-resistant cells. My study aimed to examine the role and regulation of ER stress signalling and amino acid metabolism in breast cancer drug resistance. Using a combination of in vitro and in vivo models and techniques, I established the endoplasmic reticulum (ER)-stress defence modulator PERK (eIF2AK3) as a direct downstream transcriptional target of FOXO3. My work therefore reveals a chemotherapeutic drug-resistant cancer cell vulnerability in PERK as it is adaptively downregulated by FOXO3 and suggests PERK as a potential target for cancer therapy, specifically in the context of drug-resistant cancers. Pharmaceutical PERK inhibitors have demonstrated anticancer activities in combination therapies, but their effectiveness as a single agent is limited, suggesting the existence of possible compensatory cellular responses. I found that the eIF2 kinases, PERK and GCN2 (eIF2AK4) function cooperatively to regulate cancer cell clonal renewal as well as cytotoxic drug resistance. Further analysis showed that FOXO3 modulates PERK-GCN2 cross-talk partially via JNK-AKT-FOXO3 axis. I also found GCN2 cooperates with PERK through the JNK-FOXO3 axis in a reciprocal negative feedback loop to mediate cancer chemotherapeutic drug response and clonal survival, advocating the potential of targeting GCN2 as a therapeutic strategy for treating cancer and for overcoming drug resistance. In conclusion, this project unveils a previously unappreciated role of the two eIF2 kinases, PERK and GCN2 in cancer clonal survival and drug resistance. Moreover, my findings can have important implications on developing strategies for targeting cancer and for overcoming cancer drug resistance.Open Acces
