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Title: The SHOC2 phosphatase complex as a therapeutic target for ERK pathway inhibition in RAS-driven tumors
Author: Jones, Greg Gordon
ISNI:       0000 0004 7661 0016
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2018
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Targeted inhibition of the ERK-MAPK pathway, upregulated in the majority of human cancers, has been hindered in the clinic by drug resistance and on-target toxicity. The MRAS-SHOC2-PP1 complex plays a key, but underexplored role in RAF-ERK pathway activation, by dephosphorylating a critical inhibitory site on RAF-kinases. In this body of work we present a preferential requirement for the SHOC2-phosphatase complex, specifically for Receptor Tyrosine Kinase (RTK), and anchorage-independent (tumorigenic) growth stimulated ERK-activation. We highlight that this context-dependent signalling bias has functional consequences in RAS-mutant cells, by specifically inhibiting anchorage-independent, but not 2D-adhered cell growth. Strikingly we show in vivo that SHOC2 deletion suppresses tumour initiation in KRAS-driven lung cancer models, and significantly extends overall survival. Additionally, SHOC2 inhibition selectively sensitizes KRAS- and EGFR-mutant Non-small cell lung carcinoma (NSCLC) cells to MEK inhibitors. Mechanistically we show this is because SHOC2 is required for feedback-induced RAF dimerization, and as such combined MEK inhibition and SHOC2 suppression leads to more potent and sustained ERK-pathway repression, driving a BIM-dependent apoptosis. Crucially, systemic SHOC2 ablation in adult mice is relatively well tolerated compared with other, core, ERK-pathway signalling nodes. These results present a rationale for the generation of SHOC2 targeted therapies, both as a monotherapy, and to widen the therapeutic index of MEK inhibitors.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available