Publications by authors named "Eamonn Morrison"

5 Publications

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3D Functional Genomics Screens Identify CREBBP as a Targetable Driver in Aggressive Triple-Negative Breast Cancer.

Cancer Res 2021 Jan 28. Epub 2021 Jan 28.

The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, England, United Kingdom.

Triple-negative breast cancers (TNBC) are resistant to standard-of-care chemotherapy and lack known targetable driver gene alterations. Identification of novel drivers could aid the discovery of new treatment strategies for this hard-to-treat patient population, yet studies using high-throughput and accurate models to define the functions of driver genes in TNBC to date have been limited. Here, we employed unbiased functional genomics screening of the 200 most frequently mutated genes in breast cancer, using spheroid cultures to model -like conditions, and identified the histone acetyltransferase CREBBP as a novel tumor suppressor in TNBC. CREBBP protein expression in patient tumor samples was absent in 8% of TNBCs and at a high frequency in other tumors, including squamous lung cancer, where CREBBP-inactivating mutations are common. In TNBC, CREBBP alterations were associated with higher genomic heterogeneity and poorer patient survival and resulted in upregulation and dependency on a FOXM1 proliferative program. Targeting FOXM1-driven proliferation indirectly with clinical CDK4/6 inhibitors (CDK4/6i) selectively impaired growth in spheroids, cell line xenografts, and patient-derived models from multiple tumor types with CREBBP mutations or loss of protein expression. In conclusion, we have identified CREBBP as a novel driver in aggressive TNBC and identified an associated genetic vulnerability in tumor cells with alterations in CREBBP and provide a preclinical rationale for assessing CREBBP alterations as a biomarker of CDK4/6i response in a new patient population. SIGNIFICANCE: This study demonstrates that CREBBP genomic alterations drive aggressive TNBC, lung cancer, and lymphomas and may be selectively treated with clinical CDK4/6 inhibitors.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-1822DOI Listing
January 2021

Author Correction: Lysyl oxidase drives tumour progression by trapping EGF receptors at the cell surface.

Nat Commun 2019 Jul 18;10(1):3151. Epub 2019 Jul 18.

Molecular Oncology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, M20 4BX, UK.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41467-019-11220-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639354PMC
July 2019

Lysyl oxidase drives tumour progression by trapping EGF receptors at the cell surface.

Nat Commun 2017 04 18;8:14909. Epub 2017 Apr 18.

Molecular Oncology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester M20 4BX, UK.

Lysyl oxidase (LOX) remodels the tumour microenvironment by cross-linking the extracellular matrix. LOX overexpression is associated with poor cancer outcomes. Here, we find that LOX regulates the epidermal growth factor receptor (EGFR) to drive tumour progression. We show that LOX regulates EGFR by suppressing TGFβ1 signalling through the secreted protease HTRA1. This increases the expression of Matrilin2 (MATN2), an EGF-like domain-containing protein that traps EGFR at the cell surface to facilitate its activation by EGF. We describe a pharmacological inhibitor of LOX, CCT365623, which disrupts EGFR cell surface retention and delays the growth of primary and metastatic tumour cells in vivo. Thus, we show that LOX regulates EGFR cell surface retention to drive tumour progression, and we validate the therapeutic potential of inhibiting this pathway with the small molecule inhibitor CCT365623.
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http://dx.doi.org/10.1038/ncomms14909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5399287PMC
April 2017

Utilizing Functional Genomics Screening to Identify Potentially Novel Drug Targets in Cancer Cell Spheroid Cultures.

J Vis Exp 2016 12 26(118). Epub 2016 Dec 26.

The Breast Cancer Now Toby Robins Research Centre, Division of Breast Cancer, The Institute of Cancer Research; Division of Molecular Pathology, The Institute of Cancer Research;

The identification of functional driver events in cancer is central to furthering our understanding of cancer biology and indispensable for the discovery of the next generation of novel drug targets. It is becoming apparent that more complex models of cancer are required to fully appreciate the contributing factors that drive tumorigenesis in vivo and increase the efficacy of novel therapies that make the transition from pre-clinical models to clinical trials. Here we present a methodology for generating uniform and reproducible tumor spheroids that can be subjected to siRNA functional screening. These spheroids display many characteristics that are found in solid tumors that are not present in traditional two-dimension culture. We show that several commonly used breast cancer cell lines are amenable to this protocol. Furthermore, we provide proof-of-principle data utilizing the breast cancer cell line BT474, confirming their dependency on amplification of the epidermal growth factor receptor HER2 and mutation of phosphatidylinositol-4,5-biphosphate 3-kinase (PIK3CA) when grown as tumor spheroids. Finally, we are able to further investigate and confirm the spatial impact of these dependencies using immunohistochemistry.
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http://dx.doi.org/10.3791/54738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5226468PMC
December 2016

Discovery of dapagliflozin: a potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes.

J Med Chem 2008 Mar 9;51(5):1145-9. Epub 2008 Feb 9.

Drug Safety Evaluation and Development, Bristol -Myers Squibb Company, Princeton, New Jersey 08543, USA.

The C-aryl glucoside 6 (dapagliflozin) was identified as a potent and selective hSGLT2 inhibitor which reduced blood glucose levels in a dose-dependent manner by as much as 55% in hyperglycemic streptozotocin (STZ) rats. These findings, combined with a favorable ADME profile, have prompted clinical evaluation of dapagliflozin for the treatment of type 2 diabetes.
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http://dx.doi.org/10.1021/jm701272qDOI Listing
March 2008