Simon Cook

Research Summary

One of the keys to understanding lifelong health is to understand the signalling pathways that operate inside cells and govern key fate decisions such as cell death, cell survival, cell division or cell senescence (collectively cell longevity).  These signalling pathways involve enzymes called ‘protein kinases’ that attach phosphate groups to specific cellular proteins, thereby controlling their activity, location or abundance. In this way protein kinases orchestrate the cellular response to growth factors, nutrient availability or stress and damage.

Ageing results in part from the imbalance between cellular damage, accrued throughout life, and the progressive decline in stress response and repair pathways. We are interested in how protein kinases function in stress responses, the removal of damaged cellular components (e.g. autophagy, see also Nicholas Ktistakis and Oliver Florey) and the control of cellular lifespan. We believe this will enhance our understanding of how the normal declines in these processes drive ageing.

Signalling pathways are frequently de-regulated in certain age-related diseases – notably in cancer, inflammation and neurodegeneration – and many protein kinases are attractive drug targets. Consequently we translate our basic knowledge of signalling through collaborations with charities and pharmaceutical companies (e.g. AstraZeneca and MISSION Therapeutics).

Latest Publications

Dual-mechanism ERK1/2 inhibitors exploit a distinct binding mode to block phosphorylation and nuclear accumulation of ERK1/2.
Kidger AM, Munck JM, Saini HK, Balmanno K, Minihane E, Courtin A, Graham B, O'Reilly M, Odle R, Cook SJ

The RAS-regulated RAF-MEK1/2-ERK1/2 signalling pathway is frequently deregulated in cancer due to activating mutations of growth factor receptors, RAS or BRAF. Both RAF and MEK1/2 inhibitors are clinically approved and various ERK1/2 inhibitors (ERKi) are currently undergoing clinical trials. To date ERKi display two distinct mechanisms of action (MoA); catalytic ERKi solely inhibit ERK1/2 catalytic activity, whereas dual mechanism ERKi additionally prevent the activating phosphorylation of ERK1/2 at its T-E-Y motif by MEK1/2. These differences may impart significant differences in biological activity because T-E-Y phosphorylation is the signal for nuclear entry of ERK1/2, allowing them to access many key transcription factor targets. Here, we characterised the MoA of five ERKi and examined their functional consequences in terms of ERK1/2 signalling, gene expression and anti-proliferative efficacy. We demonstrate that catalytic ERKi promote a striking nuclear accumulation of p-ERK1/2 in KRAS mutant cell lines. In contrast, dual mechanism ERKi exploit a distinct binding mode to block ERK1/2 phosphorylation by MEK1/2, exhibit superior potency and prevent the nuclear accumulation of ERK1/2. Consequently, dual-mechanism ERKi exhibit more durable pathway inhibition and enhanced suppression of ERK1/2-dependent gene expression compared to catalytic ERKi, resulting in increased efficacy across BRAF and RAS mutant cell lines.

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Molecular cancer therapeutics, 1, 1,

DOI: 10.1158/1535-7163.MCT-19-0505

PMID: 31748345

An mTORC1-to-CDK1 Switch Maintains Autophagy Suppression during Mitosis.
Odle RI, Walker SA, Oxley D, Kidger AM, Balmanno K, Gilley R, Okkenhaug H, Florey O, Ktistakis NT, Cook SJ

Since nuclear envelope breakdown occurs during mitosis in metazoan cells, it has been proposed that macroautophagy must be inhibited to maintain genome integrity. However, repression of macroautophagy during mitosis remains controversial and mechanistic detail limited to the suggestion that CDK1 phosphorylates VPS34. Here, we show that initiation of macroautophagy, measured by the translocation of the ULK complex to autophagic puncta, is repressed during mitosis, even when mTORC1 is inhibited. Indeed, mTORC1 is inactive during mitosis, reflecting its failure to localize to lysosomes due to CDK1-dependent RAPTOR phosphorylation. While mTORC1 normally represses autophagy via phosphorylation of ULK1, ATG13, ATG14, and TFEB, we show that the mitotic phosphorylation of these autophagy regulators, including at known repressive sites, is dependent on CDK1 but independent of mTOR. Thus, CDK1 substitutes for inhibited mTORC1 as the master regulator of macroautophagy during mitosis, uncoupling autophagy regulation from nutrient status to ensure repression of macroautophagy during mitosis.

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Molecular cell, S1097-2765, 19,

DOI: 10.1016/j.molcel.2019.10.016

PMID: 31733992

Targeting melanoma's MCL1 bias unleashes the apoptotic potential of BRAF and ERK1/2 pathway inhibitors.
Sale MJ, Minihane E, Monks NR, Gilley R, Richards FM, Schifferli KP, Andersen CL, Davies EJ, Vicente MA, Ozono E, Markovets A, Dry JR, Drew L, Flemington V, Proia T, Jodrell DI, Smith PD, Cook SJ

BRAF and MEK1/2 inhibitors are effective in melanoma but resistance inevitably develops. Despite increasing the abundance of pro-apoptotic BIM and BMF, ERK1/2 pathway inhibition is predominantly cytostatic, reflecting residual pro-survival BCL2 family activity. Here, we show that uniquely low BCL-X expression in melanoma biases the pro-survival pool towards MCL1. Consequently, BRAF or MEK1/2 inhibitors are synthetic lethal with the MCL1 inhibitor AZD5991, driving profound tumour cell death that requires BAK/BAX, BIM and BMF, and inhibiting tumour growth in vivo. Combination of ERK1/2 pathway inhibitors with BCL2/BCL-w/BCL-X inhibitors is stronger in CRC, correlating with a low MCL1:BCL-X ratio; indeed the MCL1:BCL-X ratio is predictive of ERK1/2 pathway inhibitor synergy with MCL1 or BCL2/BCL-w/BCL-X inhibitors. Finally, AZD5991 delays acquired BRAFi/MEKi resistance and enhances the efficacy of an ERK1/2 inhibitor in a model of acquired BRAFi + MEKi resistance. Thus combining ERK1/2 pathway inhibitors with MCL1 antagonists in melanoma could improve therapeutic index and patient outcomes.

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Nature communications, 10, 1,

PMID: 31727888

01223 496453

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stress responses