Activation of Aurora Kinase A by DNA damage - understanding the signalling pathway to improve radiotherapy response

"Radiation is a mainstay of cancer therapy, however radioresistance is a significant challenge in the treatment of locally advanced, recurrent and metastatic cancers. Novel ways to improve radiation response in hard to treat cancers are urgently needed.

We find that clinical inhibitors of the serine/threonine kinase Aurora A (AURKA) are cancer cell radiosensitizers, and that AURKA overexpression correlates with radioresistance in cancer, including lung cancer. Interestingly, AURKA is activated with delayed kinetics following DNA damage induced by ionizing radiation. This exciting studentship focuses on phosphoproteomic approaches for identification and characterization of functionally relevant AURKA-dependent signaling pathways activated by DNA damage (including ionizing radiation). The project will provide new, mechanistic insights into the role of AURKA following DNA damage, and will ultimately complement and guide future pre-clinical studies.

Specific objectives: (1) Quantitative proteomic analysis of the DNA damage response and (phospho)proteome following Radiation-induced DNA damage. (2) Pathway and target analysis of AURKA activation and inactivation and downstream target activation after DNA damage and (3) In vivo analysis of AURKA signaling networks relevant to tumour radiotherapy.

Experimental Approach: The studentship offers a unique training opportunity in a broad range of skills involved in pre-clinical drug development, including SILAC and TMT-based Mass spectroscopy biochemical and cell biology assays (such as DNA damage, cell cycle and in vitro kinase assays) and in vivo analysis of AURKA and its downstream targets in patient material (Non Small Cell Lung Cancer (NSCLC) specimens).

Environment: In Sheffield the student will be part of the Bryant lab, a supportive, dynamic multidisciplinary team spanning chemists to clinical fellows, who are all working together to develop better treatments for cancer. In particular the student will work in parallel to a clinical fellow who is currently evaluating the clinical implications of AURKA inhibition and developing clinical trails of radiosenstizing agents. You will also benefit from being part of the wider research within Sheffield as part of the Sheffield Institute for Nucleic Acids and Sheffield ECMC centers. The student will also spend time training in the Eyers lab in the Centre for Proteome Research, a state of the art mass-spectrometry facility at University of Liverpool. Here the student will join a vibrant group of biochemists involved in developing novel techniques for analyzing signaling pathways."