Project ID CM-HD2024_17


Co Supervisor 1A Faculty of Life Sciences & Medicine, School of Basic & Medical Biosciences, Randall Centre for Cell & Molecular BiophysicsWebsite

Co Supervisor 1B Faculty of Life Sciences & Medicine, School of Basic & Medical Biosciences, Randall Centre for Cell & Molecular BiophysicsWebsite

Targeting the p90 Ribosomal S6 Kinases Pathways in Prostate Cancer: from Structure to Function

Prostate Cancer (PCa) is the most commonly diagnosed cancer in men, with nearly 140 new cases a day in UK. Patients are treated with drugs that reduce the level of the male sex hormone or block its activity, thus preventing the activation of the Androgen Receptor, the main driver of PCa cells growth and proliferation. Despite initial remission, the high frequency of disease progression to aggressive and therapy resistant stages (termed Castrate-Resistant Prostate Cancer) has led to the search for new therapeutic targets. The p90 ribosomal S6 kinase (RSKs) family is a group of kinases that holds promise as a novel target. In fact, we have recently shown that RSKs are highly expressed in PCa, which is correlated with enhanced cancer cells proliferation. However, the molecular mechanisms behind these cellular processes remain unknown.

Aim: This project proposes to characterise the structure and function of the RSKs and examine their role in driving PCa disease progression, thereby validating inhibition of RSKs as a strategy for the treatment of PCa.

Year 1: Determine PCa-specific RSKs activation and drug inhibition mechanisms.
Year 1-3: Sample preparation and structural determination of RSKs in complex with different PCa-specific substrates using single-particle cryo-electron microscopy.
Year 3: Validate in PCa and CRPC cell lines the role these RSKs complexes have in driving cell proliferation and drug resistance.

This project is a collaboration between the Prischi lab, which uses biochemical and cellular techniques to study protein-protein and protein-ligand interactions, and the Atherton lab, which uses cutting-edge cryo-EM and image-processing techniques (including AI). The student will acquire advanced skills in cancer research, and expertise in molecular and cellular biology, structure determination and image-processing. Complemented by Departmental lectures/seminars, and workshops on career, communication, writing and publishing.

Representative Publications

1. Chrysostomou, S. et al. Repurposed floxacins targeting RSK4 prevent chemoresistance and metastasis in lung and bladder cancer. Science Translational Medicine (2021) doi: 10.1126/scitranslmed.aba4627 2. Cronin, R., Brooke, G. N. & Prischi, F. The role of the p90 ribosomal S6 kinase family in prostate cancer progression and therapy resistance. Oncogene (2021) doi:10.1038/s41388-021-01810-9
1. Atherton, J et al., The mechanism of kinesin inhibition by kinesin-binding protein. Elife (2020) doi: 10.7554/eLife.61481. 2. Atherton J et al., Structural determinants of microtubule minus end preference in CAMSAP CKK domains. Nat Comms (2019) doi: 10.1038/s41467-019-13247-6. 3. Atherton J et al., A structural model for microtubule minus-end recognition and protection by CAMSAP proteins. Nat Struct Mol Biol (2017) doi: 10.1038/nsmb.3483.