Dr Catherine Lindon - Group leader, Deputy Head of Department
Fellow of Newnham College
E-Mail: acl34 [at] cam.ac.uk
Tel: +44 1223 333964
Keywords
Ubiquitin, APC/C, Aurora kinase, cell cycle, TPD, PROTACs
Research summary
We study the cell biology of ubiquitin-mediated proteolysis, the process by which cells dispose of their unwanted proteins. This is an essential pathway in cell division, which is coordinated by the Anaphase-Promoting Complex (APC/C) ubiquitin ligase complex. APC/C marks proteins with ubiquitin so that they are recognised and destroyed by the proteasome. One key target of APC/C is Aurora A kinase (AURKA), a major regulator of the cell cycle whose activity levels are an important output of APC/C activity in interphase. We have studied AURKA extensively over the years, both as a model substrate of the APC/C that can be used to study substrate-specific determinants of APC/C activity, but also as a well-known therapeutic target in cancer drug development, since overexpression of AURKA is strongly associated with several types of cancer, and with acquired resistance to cancer therapies. Work from the lab has contributed to our understanding of how AURKA’s regulation by APC/C contributes to stability, activity and function through the cell cycle.
We are also focused on the development of AURKA PROTACs as a potentially superior therapeutic strategy to traditional ATP-competitive inhibitors. PROTACs are innovative tools that harness the cell’s ubiquitin signaling pathways to eliminate harmful proteins. AURKA PROTACs are able to suppress critical kinase-independent roles, such as its structural scaffolding of oncoprotein N-Myc. The targeted protein degradation approach is uniquely capable of eliminating the nuclear oncogenic pool of AURKA found in interphase cancer cells—a population associated with poor prognosis and drug resistance that promotes transcriptional programs for stemness and hypoxia. Research in the lab has demonstrated that PROTACs offer precision through localized degradation, selectively targeting AURKA on the mitotic spindle while leaving the centrosomal pool intact. PROTAC sensitivity is governed by cellular parameters like the deubiquitinase OTUD6A, which in interphase cells protects cytoplasmic AURKA from degradation while leaving the nuclear pool vulnerable. PROTACs may therefore serve as potent treatments for malignancies by overcoming the clinical limitations of current inhibitors like alisertib, whilst providing essential investigational tools for defining the cellular mechanisms that regulate protein stability.
We are also exploiting our knowledge of ubiquitin signaling to design novel APC/C tools, in a longstanding collaboration with Prof Itzhaki’s lab in the department. These tools include biodegraders and other Targeted Protein Degradation tools designed to eliminate proteins responsible for neurodegenerative diseases. Ultimately, my research group seeks to transform our understanding of protein stability into viable therapeutic strategies.
Our research is currently funded by the BBSRC, Rosetrees Trust and David James Trust. We acknowledge the MRC, Cancer Research UK, AstraZeneca and Royal Society for past support.