Research

Kinases are attractive therapeutic targets for cancer. Approximately 25% of the known 535 kinases are associated with cancer through mutation, overexpression or aberrant signalling. However, the majority of therapies targeting kinases in cancer patients fail, due to development of resistance, or toxicity. We are working to develop new approaches to target cancer kinases to overcome these limitations.

We have described a novel mechanism by which kinase substrate specificity is regulated. Modification of the kinase activation loop by phosphorylation or mutation can alter substrate specificity. In cancer, this can lead to the rewiring of signalling pathways to promote oncogenic properties. How substrate specificity is determined, particularly relating to activation-loop modification is a hitherto unexplored niche which will provide new insights in the targeting of kinases in cancer.

This now provides an exciting opportunity to significantly advance understanding of the fundamental biology of kinase regulation. These new insights will enable the discovery of previously unknown or undefined signalling nodes and establish a route to developing new kinase inhibitors for personalised cancer therapy through the delivery of a high-resolution understanding of kinase regulation and dysregulation in cancer.

Major Funding

• 2024-2027 – MRC-New Investigator Research Grant (£876,294) ‘Investigating cell cycle vulnerabilities in TP53 mutant cancers’
• 2023-2027 – MRC-DTP studentship (£96,000) 'Signal rewiring of the DNA Damage Pathway'
• 2023-2024 – Barts Charity Seed Funding (£59,077) ’Targeting a mitotic failsafe pathway in high grade serous ovarian cancer’
• 2023-2025 – AMS Springboard (£99,998) ‘New rules of engagement – Precision mapping of substrates to understand kinase specificity’
• 2022-2026 – Cancer Research UK City of London Centre PhD studentship (£146,443) 'Targeting Aurora B in the Topo2-dependent G2 checkpoint as a novel tumour-specific vulnerability'
• 2021-2022 – European Proteomics Infrastructure Consortium (EPIC-XS), approx.£20,000 (in kind) for access to state of the art proteomics facilities - ‘A comprehensive phosphoproteome of               the cell cycle’
• 2021-2022 – Royal Society Research Grant (£19,772) ‘A comprehensive phosphoproteome of the cell cycle’
• 2020-2024 – BBSRC-LIDo Studentship (£84,140) 'Exploring kinase substrate selectivity and novel mechanisms of kinase regulation'
• 2020-2023 – Barts Cancer Institute, Early career researcher (£411,280) ‘New approaches to targeting kinases in cancer’

Recent Publications

Cell cycle responses to Topoisomerase II inhibition: Molecular mechanisms and clinical implications Soliman TN, Keifenheim D, Parker PJ et al. Journal of Cell Biology (2023) 222(10) e202209125

Genome-protective topoisomerase 2a-dependent G2 arrest requires p53 in hTERT-positive cancer cells Lockwood N, Martini S, Lopez-Pardo A et al. Cancer Research (2022) 82(10) 1762-1773

Co-ordinated control of the Aurora B abscission checkpoint by PKCε complex assembly, midbody recruitment and retention Watson L, Soliman TN, Davis K et al. Biochemical Journal (2021) 478(10) 2247-2263

Author Correction: The Aurora B specificity switch is required to protect from non-disjunction at the metaphase/anaphase transition (Nature Communications, (2020), 11, 1, (1396), 10.1038/s41467-020-15163-6) Kelly JR, Martini S, Brownlow N et al. Nature Communications (2020) 11(1)

Equivocal, explicit and emergent actions of PKC isoforms in cancer Parker PJ, Brown SJ, Calleja V et al. Nature Reviews Cancer (1)

A cancer-associated, genome protective programme engaging PKCε Parker PJ, Lockwood N, Davis K et al. Advances in Biological Regulation (2020) 78(10) 100759

Specific mechanisms of chromosomal instability indicate therapeutic sensitivities in high-grade serous ovarian carcinoma. Mcclelland S, Tamura N, Shaikh N et al. Cancer Research (2020) (1)

The Aurora B specificity switch is required to protect from non-disjunction at the metaphase/anaphase transition Kelly JR, Martini S, Brownlow N et al. Nature Communications 11(10) 1396

A genome-wide RNAi screen identifies the SMC5/6 complex as a non-redundant regulator of a Topo2a-dependent G2 arrest Deiss K, Lockwood N, Howell M et al. Nucleic Acids Research (2019) 47(10) gky1295-

Inhibitor-induced HER2-HER3 heterodimerisation promotes proliferation through a novel dimer interface Claus J, Patel G, Autore F et al. eLife 7(10) e32271

For additional publications, please click here

Team

Postdoctoral Researchers

• Dr Irina Titkova

Biography

I completed my Bachelor of Science at the University of Queensland, Australia, before going on to an Honours program at the Queensland Institute for Medical Research. I attained my PhD from the University of Queensland, studying the role of MAP kinase signalling in the cell cycle and mitosis with Professor Brian Gabrielli. After completing my PhD, I moved to London to start a Postdoctoral Fellowship with Professor Peter Parker initially at the CRUK London Research Institute, Lincolns Inn Fields and then moving to the Francis Crick Institute when it opened in 2015.  Here I investigated the genome protective role of the kinase PKCε, in the cell cycle. In 2019, I commenced a postdoc with Dr Sarah McClelland here at Barts Cancer Institute, researching chromosomal instability in High Grade Serous Ovarian Cancer and started my own independent laboratory at BCI in July 2020.