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Abstract
The maturing mutational landscape of cancer genomes, the development and application of clinical interventions and evolving insights into tumour-associated functions reveal unexpected features of the protein kinase C (PKC) family of serine/threonine protein kinases. These advances include recent work showing gain or loss-of-function mutations relating to driver or bystander roles, how conformational constraints and plasticity impact this class of proteins and how emergent cancer-associated properties may offer opportunities for intervention. The profound impact of the tumour microenvironment, reflected in the efficacy of immune checkpoint interventions, further prompts to incorporate PKC family actions and interventions in this ecosystem, informed by insights into the control of stromal and immune cell functions. Drugging PKC isoforms has offered much promise, but when and how is not obvious.
This Review discusses protein kinase C (PKC) isoforms in cancer, in particular focusing on their functional properties in the context of tumour suppression or promotion, target validation, PKC pharmacology and therapeutic exploitation.
Details
; Brown, Sophie J 2 ; Calleja Veronique 2 ; Chakravarty Probir 3 ; Cobbaut Mathias 2
; Linch, Mark 4 ; Marshall Jacqueline J T 2
; Martini, Silvia 2 ; McDonald, Neil Q 5 ; Soliman, Tanya 6
; Watson, Lisa 2 1 Francis Crick Institute, Protein Phosphorylation Laboratory, London, UK (GRID:grid.451388.3) (ISNI:0000 0004 1795 1830); King’s College London, Guy’s Campus, School of Cancer and Pharmaceutical Sciences, London, UK (GRID:grid.13097.3c) (ISNI:0000 0001 2322 6764)
2 Francis Crick Institute, Protein Phosphorylation Laboratory, London, UK (GRID:grid.451388.3) (ISNI:0000 0004 1795 1830)
3 The Francis Crick Institute, Bioinformatics, London, UK (GRID:grid.451388.3) (ISNI:0000 0004 1795 1830)
4 UCL Cancer Institute, University College London, London, UK (GRID:grid.83440.3b) (ISNI:0000000121901201)
5 Francis Crick Institute, Signalling and Structural Biology Laboratory, London, UK (GRID:grid.451388.3) (ISNI:0000 0004 1795 1830); Birkbeck College, Institute of Structural and Molecular Biology, Department of Biological Sciences, London, UK (GRID:grid.88379.3d) (ISNI:0000 0001 2324 0507)
6 Bart’s Cancer Institute, Centre for Cancer Genomics and Computational Biology, London, UK (GRID:grid.88379.3d)