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Monday, October 21 • 3:15pm - 3:25pm
Lost in Translation: Success through Collaboration- Utilizing 3-Dimensional Functional Genomics Screening to Identify CREBBP as a Novel Tumour Suppressor in Breast Cancer

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Rationale - The contribution of the majority of frequently mutated genes to tumourigenesis is not fully defined. Many aggressive human cancers, such as triple negative breast cancers (TNBCs), have a poor prognosis and lack tractable biomarkers and targeted therapeutic options.

Methods - Here, we systematically characterize loss-of-function mutations to generate a functional map of novel driver genes in a 3-dimensional (3D) model of breast cancer heterogeneity that more readily recapitulates the unfavourable tumour microenvironment in vivo i.e. nutrient stress.

Results - We identified several genes, including CREBBP, FOXA1, KMT2C and NIPBL, whose silencing provided a 3D specific growth advantage. Indeed, the histone acetyltransferase CREBBP was a potent tumour suppressor gene whose silencing provided a 3D-specific growth advantage only under oxygen and nutrient deplete conditions.

CREBBP protein expression was altered in a third of TNBCs as well as several other solid tumours, including bladder, ovarian and squamous lung cancers. In multiple primary tumours and cell models, loss of CREBBP activity resulted in upregulation of the FOXM1 transcriptional network. Strikingly, treatment with a range of CDK4/6 inhibitors (CDK4/6i), that indirectly target FOXM1 activity, selectively impaired growth in both CREBBP-altered spheroids, patient-derived organoids and cell line xenografts from multiple tumour types.

Conclusions - This study is the first to provide rationale for CREBBP as a biomarker for CDK4/6i response in cancer representing a new treatment paradigm for tumours that harbour CREBBP alterations that have limited therapeutic options.

Authors - Barrie Peck, Philip Bland, Ioanna Mavrommati, Hannah Cottom, Patty T Wai, Sarah L Maguire, Holly E Barker, Eamonn Morrison, Divya Kriplani, Lu Yu, Amy Gibson, Giulia Falgari, Keith Brennan, Gillian Farnie, Rebecca Marlow, Daniela Kolarevic, Snezana Susnjar, Natasa Medic Milijic, Kalnisha Naidoo, Patrycja Gazinska, Ioannis Roxanis, Sunil Pancholi, Lesley-Ann Martin, Erle M Holgersen, Maggie CU Cheang, Farzana Noor, Sophie Postel-Vinay, Gerard Quinn, Simon McDade, Lukas Krasny, Paul Huang, Frances Daley, Gareth Muirhead, Syed Haider, Fredrik Wallberg, Jyoti S. Choudhary, Andrew N Tutt, & Rachael Natrajan

Speakers
avatar for Barrie	Peck, Ph.D.

Barrie Peck, Ph.D.

Group Leader, Barts Cancer Institute
I completed my Ph.D. in breast cancer signalling at Imperial College London in 2010. I then moved to the London Research Institute to the lab of Prof. Almut Schulze to study cancer metabolism. This work focussed on identifying novel cancer-specific dependencies in cancer metabolism... Read More →

Chair

Monday October 21, 2019 3:15pm - 3:25pm
Wellcome Auditorium