3D Functional Genomics Screens Identify CREBBP as a Targetable Driver in Aggressive Triple-Negative Breast Cancer.
3D Functional Genomics Screens Identify CREBBP as a Targetable Driver in Aggressive Triple-Negative Breast Cancer.
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DOI：
10.1158/0008-5472.can-20-1822
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发表时间：
2021-02-15
期刊：
影响因子：
11.2
通讯作者：
Natrajan R
中科院分区：
文献类型：
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作者：
Peck B;Bland P;Mavrommati I;Muirhead G;Cottom H;Wai PT;Maguire SL;Barker HE;Morrison E;Kriplani D;Yu L;Gibson A;Falgari G;Brennan K;Farnie G;Buus R;Marlow R;Novo D;Knight E;Guppy N;Kolarevic D;Susnjar S;Milijic NM;Naidoo K;Gazinska P;Roxanis I;Pancholi S;Martin LA;Holgersen EM;Cheang MCU;Noor F;Postel-Vinay S;Quinn G;McDade S;Krasny L;Huang P;Daley F;Wallberg F;Choudhary JS;Haider S;Tutt AN;Natrajan R
三阴性乳腺癌（TNBC）对标准治疗化疗具有抗性，并且缺乏已知的靶向驱动基因改变。识别新的驱动基因可以帮助发现这种难以治疗的患者群体的新治疗策略，但迄今为止，使用高通量和准确模型来定义TNBC中驱动基因功能的研究有限。在这里，我们采用无偏见的功能基因组学筛选乳腺癌中200个最常见的突变基因，使用球体培养物来模拟体内样条件，并确定组蛋白乙酰转移酶CREBBP作为TNBC中的新型肿瘤抑制因子。患者肿瘤样本中CREBBP蛋白表达在8%的TNBC中不存在，在其他肿瘤中频率很高，包括鳞状肺癌，其中CREBBP失活突变很常见。在TNBC中，CREBBP改变与较高的基因组异质性和较差的患者存活率相关，并导致上调和对FOXM 1增殖程序的依赖。用临床CDK 4/6抑制剂间接靶向FOXM 1驱动的增殖，选择性地损害了来自具有CREBBP突变或蛋白表达缺失的多种肿瘤类型的球状体、细胞系异种移植物和患者来源模型的生长。总之，我们已经将CREBBP确定为侵袭性TNBC的新驱动因素，并确定了肿瘤细胞中与CREBBP改变相关的遗传脆弱性，并为评估CREBBP改变作为新患者人群中CDK 4/6抑制剂反应的生物标志物提供了临床前依据。
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 in vivo 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 eight percent of TNBC 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 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 tumour cells with alterations in CREBBP and provide a pre-clinical rationale for assessing CREBBP alterations as a biomarker of CDK4/6 inhibitor response in a new patient population.