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

Barrie Peck, Philip Bland, Ioanna Mavrommati, Gareth Muirhead, 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, Richard Buus, Rebecca Marlow, Daniela Novo, Eleanor Knight, Naomi GuppyDaniela Kolarevic, Snezana Susnjar, Natasa Medic Milijic, Kalnisha Naidoo, Patrycja Gazinska, Ioannis Roxanis, Sunil Pancholi, Lesley-Ann Martin, Erle M Holgersen, Maggie C U Cheang, Farzana Noor, Sophie Postel-Vinay, Gerard Quinn, Simon McDade, Lukas Krasny, Paul Huang, Frances Daley, Fredrik Wallberg, Jyoti S Choudhary, Syed Haider, Andrew N Tutt, Rachael Natrajan

Research output: Contribution to journalArticlepeer-review

Abstract

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.
Original languageEnglish
Pages (from-to)847-859
Number of pages13
JournalCancer Research
Volume81
Issue number4
Early online date28 Jan 2021
DOIs
Publication statusPublished - Feb 2021

Fingerprint

Dive into the research topics of '3D Functional Genomics Screens Identify CREBBP as a Targetable Driver in Aggressive Triple-Negative Breast Cancer'. Together they form a unique fingerprint.

Cite this