在非小细胞肺癌中，SMARCA4 缺失与 CDK4/6 抑制具有综合致死性。,Nature Communications

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在非小细胞肺癌中，SMARCA4 缺失与 CDK4/6 抑制具有综合致死性。
Nature Communications ( IF 14.7 ) Pub Date : 2019-02-04 , DOI: 10.1038/s41467-019-08380-1
Yibo Xue _{1,

2} , Brian Meehan ₃ , Zheng Fu _{1,

2} , Xue Qing D Wang ₁ , Pierre Olivier Fiset ₄ , Ralf Rieker ₅ , Cameron Levins ₆ , Tim Kong _{1,

2} , Xianbing Zhu _{1,

2} , Geneviève Morin _{1,

2} , Lashanda Skerritt _{1,

2} , Esther Herpel ₇ , Sriram Venneti ₈ , Daniel Martinez ₉ , Alexander R Judkins ₁₀ , Sungmi Jung ₄ , Sophie Camilleri-Broet ₄ , Anne V Gonzalez ₁₁ , Marie-Christine Guiot ₁₂ , William W Lockwood _{13,

14,

15} , Jonathan D Spicer ₁₆ , Abbas Agaimy ₅ , William A Pastor _{1,

2} , Josée Dostie ₁ , Janusz Rak ₃ , William D Foulkes _{6,

17,

18} , Sidong Huang _{1,

2}

Affiliation

Department of Biochemistry, McGill University, Montreal, QC, H3G 1Y6, Canada.
The Rosalind & Morris Goodman Cancer Research Centre, McGill University, Montreal, QC, H3A 1A3, Canada.
Department of Pediatrics, McGill University, and Research Institute of McGill University Health Centre, Montreal Children's Hospital, Montreal, QC, H4A 3J1, Canada.
Department of Pathology, Glen Site, McGill University Health Centre, Montreal, QC, H4A 3J1, Canada.
Institute of Pathology, Friedrich-Alexander-University Erlangen-Nürnberg, University Hospital, 91054, Erlangen, Germany.
Department of Human Genetics, McGill University, Montreal, QC, H3A 0C7, Canada.
Tissue Bank of the National Center for Tumor Diseases (NCT) Heidelberg, and Institute of Pathology, Heidelberg University Hospital, 69120, Heidelberg, Germany.
Pathology and Neuropathology, University of Michigan Medical School, Ann Arbor, MI, 48109-0605, USA.
Children's Hospital of Philadelphia Research Institute, Philadelphia, PA, 19104, USA.
Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Keck School of Medicine of University of Southern California, Los Angeles, CA, 90027, USA.
Division of Respiratory Medicine, Montreal Chest Institute, McGill University Health Centre, Montreal, QC, H4A 3J1, Canada.
Department of Pathology, Montreal Neurological Hospital/Institute, McGill University Health Centre, Montreal, QC, H4A 3J1, Canada.
Department of Integrative Oncology, British Columbia Cancer Agency, Vancouver, BC, V5Z 1L3, Canada.
Interdisciplinary Oncology Program, University of British Columbia, Vancouver, BC, V6T 1Z2, Canada.
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, V6T 2B5, Canada.
Department of Surgery, McGill University Health Center, Montreal, QC, H4A 3J1, Canada.
Department of Medical Genetics, and Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC, H3T 1E2, Canada.
Department of Medical Genetics and Cancer Research Program, Research Institute of the McGill University Health Centre, McGill University, Montreal, QC, H4A 3J1, Canada.

肿瘤抑制基因 SMARCA4 (BRG1) 是一种关键的 SWI/SNF 染色质重塑基因，在癌症中经常失活，并且不能直接用于药物治疗。我们最近发现，卵巢癌亚型中 SMARCA4 缺失会导致细胞周期蛋白 D1 缺乏，从而导致对 CDK4/6 抑制的敏感性。在这里，我们发现这种脆弱性在非小细胞肺癌 (NSCLC) 中是保守的，其中 SMARCA4 丢失还会导致细胞周期蛋白 D1 表达减少以及对 CDK4/6 抑制剂的选择性敏感性降低。此外，SMARCA2（在 NSCLC 子集中丢失的另一个 SWI/SNF 亚基）也在 SMARCA4 缺失时调节细胞周期蛋白 D1 和药物反应。从机制上讲，SMARCA4/2 缺失通过限制 CCND1 染色质可及性和抑制 CCND1 转录激活因子 c-Jun 的组合来减少细胞周期蛋白 D1 的表达。此外，无论是在体外还是体内，SMARCA4 的丢失对于 CDK4/6 抑制都是合成致死的，这表明 FDA 批准的 CDK4/6 抑制剂可以有效治疗这一重要的 NSCLC 亚组。

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更新日期：2019-02-05

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