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Therapeutic potential of SHOC2 via its selective contribution of the ERK pathway activation

Boned del Río, Isabel; (2019) Therapeutic potential of SHOC2 via its selective contribution of the ERK pathway activation. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

ERK signalling pathway is hyperactivated in the majority of human cancers and consequently, countless efforts have been made to target its components. However, drug resistance and on-target toxicity have severely limited the clinical efficacy of current ERK pathway inhibitors. The SHOC2-MRAS-PP1 phosphatase complex (SHOC2 complex) plays a key role in ERK pathway regulation by dephosphorylating a conserved inhibitory site (‘S259’) in the RAF molecules. Gain-of-function mutations in the three subunits of the complex as well as in CRAF around the S259 site found in Noonan syndrome independently validate the importance of this activating step. However, ‘S259’ RAF dephosphorylation is transitory and re-phosphorylation by different kinases reverses the activation of RAF molecules. According to our data, the SHOC2 complex is essential for EGF-stimulated RAF heterodimerization and selectively contributes to ERK activation in a context-dependent manner. SHOC2-independent mechanisms of ERK activation involving CRAF activation by N-region phosphorylation make SHOC2 redundant for normal proliferation in 2D and likely account for tissue homeostasis in adult mice. However, oncogenic KRAS signalling favours SHOC2-mediated ERK activation, which is consistent with the requirement of SHOC2 for anchorage-independent proliferation and lung tumour growth of KRAS mutant cells in syngeneic transplantable mouse models of lung colonisation. In addition, SHOC2 deletion selectively sensitises murine KRAS mutant cells to MEK inhibitors. In vivo, combined SHOC2 ablation and MEK inhibitor treatment leads to apoptosis-mediated tumour regression in syngeneic KRAS mutant transplantable mouse models. Collectively, our results provide a rationale for targeting the SHOC2 holophosphatase in RAS-driven cancers, both as a monotherapy or in combination with MEK inhibitors.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Therapeutic potential of SHOC2 via its selective contribution of the ERK pathway activation
Event: UCL (University College London)
Language: English
Additional information: Copyright © The Author 2019. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
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/10088429
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