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The SHOC2 phosphatase complex as a therapeutic target for ERK pathway inhibition in RAS-driven tumors

Jones, Greg Gordon; (2018) The SHOC2 phosphatase complex as a therapeutic target for ERK pathway inhibition in RAS-driven tumors. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

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.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: The SHOC2 phosphatase complex as a therapeutic target for ERK pathway inhibition in RAS-driven tumors
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Third party copyright materila has been removed from ethesis.
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Cancer Bio
URI: https://discovery.ucl.ac.uk/id/eprint/10060157
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