Cancer cells are often hallmarked by stress but take advantage of intrinsic protein homeostasis mechanisms to increase their resistance to stress-induced cell death. Multiple myeloma (MM) cancer cells rely heavily on endoplasmic reticulum-associated degradation (ERAD) to decrease the toxic levels of misfolded proteins that cause stress. Current therapeutic agents create more stress to induce MM cell death, but the robust and dynamically responsive ERAD mechanism elevates resistance to them which unwittingly supports cancer progression. The research will build on John’s previous work in proteostasis and ubiquitin biology to establish ERAD mediated by the Hrd1 ubiquitin ligase complex as a new therapeutic target in cancer.
“This Fellowship is going to allow me to explore a new strategy for cancer intervention,” said John. “By understanding the fundamental nature of complexes responsible for protein degradation and the dynamic adaptability of quality control mechanisms, we can leverage that insight to develop compounds that impair or augment ERAD as a way to stop cancer cells from being able to grow.”
John has become a world-leader in his field researching the molecular mechanisms underpinning protein quality control in the ER, and in particular how specific substrates are identified and degraded by ER-associated ubiquitin ligases.
Head of Department Professor Andrew Carr commented: “This exciting programme has the potential to lay the groundwork for the identification of new targets that may prove valuable for therapeutic intervention in cancer and other diseases associated with dysfunctional proteostasis, such as diabetes and neurodegeneration.”
Cancer Research UK Senior Fellowships support group leaders to further develop their own research programme and build their reputation as a world-leader in their cancer research field.
The research will start in January 2020 and run for six years.