Protein kinases represent the largest group of drug targets in cancer therapy. My research focuses on kinases regulating cancer cell growth and motility to understand how and when to target them with drugs.
Disruption of pancreatic stellate cell myofibroblast phenotype promotes pancreatic tumor invasion. Cell Reports (2022) 38(4):110227. PMID: 35081338
Inhibitor-induced HER2-HER3 heterodimerisation promotes proliferation through a novel dimer interface. Elife (2018) 7. pii: e32271. PMID: 29712619
Knockout of the PKN family of Rho effector kinases reveals a non-redundant role for PKN2 in developmental mesoderm expansion. Cell Reports (2016) 14(3):440-448. PMID: 26774483
mTORC2 targets AGC kinases through Sin1-dependent recruitment. Biochem J (2011) 439(2):287-97. PMID: 21806543
PKC maturation is promoted by nucleotide pocket occupation independently of intrinsic kinase activity. Nat Struct Mol Biol (2009) 16(6):624-30. PMID: 19465915
The targeting of protein kinases represents an opportunity and challenge in cancer treatment. Some 2% of transcribed genes are kinases, many implicated in tumorigenesis and all potentially druggable.
My research encompasses various cancer associated kinases, including PKC, PKN, mTOR and EGFR family tyrosine kinases. In particular, my work on PKC and the HER family of tyrosine kinase growth factor receptors has revealed that inhibitors can have surprising allosteric effects on kinase function with significant implications for therapy.
My group is currently examining the role of the PKN kinases in malignant progression. PKN kinases are effectors of Rho family GTPases, regulating cell shape, adhesion and motility. Our studies on the role for PKN family members in mammalian development has provided significant insight; we have described a key non-redundant role for the PKN2 isoform in the regulation of embryo morphogenesis, cell proliferation and migration; phenotypes critically linked to cancer progression (Cell Reports 2016).
The PKN kinases are dramatically upregulated in many cancers and high expression has been correlated with metastatic disease – the spread of cancer around the body. Our current studies focus on the stromal roles for the PKN kinases in pancreatic and breast cancer, supported by the novel roles we have discovered for PKN during development.
The ultimate goal of this research is to assess whether these kinases represent a significant cancer drug target.
Opposing roles for ADAMTS2 and ADAMTS14 in myofibroblast differentiation and function Carter E, Yoneten K, Gavara N et al. (2022) (18)
Cancer-associated fibroblasts in pancreatic cancer: new subtypes, new markers, new targets Menezes S, Okail MH, Jalil SMA et al. Journal of Pathology (2022) 257(7) 526-544
PKN2 deficiency leads both to prenatal ‘congenital’ cardiomyopathy and defective angiotensin II stress responses Marshall JJT, Cull JJ, Alharbi HO et al. Biochemical Journal (2022) 479(7) 1467-1486
Disruption of pancreatic stellate cell myofibroblast phenotype promotes pancreatic tumor invasion Murray ER, Menezes S, Henry JC et al. Cell Reports (2022) 38(7)
Targeting the HER3 pseudokinase domain with small molecule inhibitors Colomba A, Claus J, Gao F et al. (2022) 667(7) 455-505
Membrane Tension Orchestrates Rear Retraction in Matrix-Directed Cell Migration Hetmanski JHR, de Belly H, Busnelli I et al. Developmental Cell (2019) 51(1) 460-475.e10
Membrane tension orchestrates rear retraction in matrix directed cell migration Hetmanski JHR, de Belly H, Nair RV et al. INTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY (2019) 100(11) A44-A45
ADORA2A-mediated protection of ischemia-reperfusion injury. Role of protein kinase N1: A new player in the pathophysiology of experimental stroke Zur Nedden S, Orset C, Haellewyn B et al. PURINERGIC SIGNALLING (2018) 14(1) S50-S50
Protein Kinase C-β Dictates B Cell Fate by Regulating Mitochondrial Remodeling, Metabolic Reprogramming, and Heme Biosynthesis Tsui C, Martinez-Martin N, Gaya M et al. Immunity (2018) 48(7) 1144-1159.e5
Inhibitor-induced HER2-HER3 heterodimerisation promotes proliferation through a novel dimer interface Claus J, Patel G, Autore F et al. eLife (2018) 7(7)For additional publications, please click here
I completed my BSc in biochemistry at the University of Bath where I got hooked on research while working on a placement year in the US on protein phosphatases and virology.
I studied for my PhD in Glasgow on a Wellcome Trust Prize studentship working on receptor mediated signal transduction, graduating in 2000. After completing a 2 years Wellcome Trust postdoctoral fellowship in Glasgow, I joined Professor Peter Parker’s lab at the Cancer Research UK London Research Institute where I studied the role PKC family protein kinases in development and cancer.
I joined Barts Cancer Institute in 2013 as an Early Career Researcher in the Centre for Tumour Biology and was promoted to Senior Lecturer in 2018.