Mu Ping, Zhang Zeda, Benelli Matteo, Karthaus Wouter R, Hoover Elizabeth, Chen Chi-Chao, Wongvipat John, Ku Sheng-Yu, Gao Dong, Cao Zhen, Shah Neel, Adams Elizabeth J, Abida Wassim, Watson Philip A, Prandi Davide, Huang Chun-Hao, de Stanchina Elisa, Lowe Scott W, Ellis Leigh, Beltran Himisha, Rubin Mark A, Goodrich David W, Demichelis Francesca, Sawyers Charles L
Human Oncology and Pathology Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
Louis V. Gerstner, Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Science. 2017 Jan 6;355(6320):84-88. doi: 10.1126/science.aah4307.
Some cancers evade targeted therapies through a mechanism known as lineage plasticity, whereby tumor cells acquire phenotypic characteristics of a cell lineage whose survival no longer depends on the drug target. We use in vitro and in vivo human prostate cancer models to show that these tumors can develop resistance to the antiandrogen drug enzalutamide by a phenotypic shift from androgen receptor (AR)-dependent luminal epithelial cells to AR-independent basal-like cells. This lineage plasticity is enabled by the loss of TP53 and RB1 function, is mediated by increased expression of the reprogramming transcription factor SOX2, and can be reversed by restoring TP53 and RB1 function or by inhibiting SOX2 expression. Thus, mutations in tumor suppressor genes can create a state of increased cellular plasticity that, when challenged with antiandrogen therapy, promotes resistance through lineage switching.
一些癌症通过一种称为谱系可塑性的机制逃避靶向治疗，即肿瘤细胞获得一种细胞谱系的表型特征，而该细胞谱系的存活不再依赖于药物靶点。我们使用体外和体内人前列腺癌模型表明，这些肿瘤可通过从雄激素受体（AR）依赖性管腔上皮细胞向AR非依赖性基底样细胞的表型转变，对抗雄激素药物恩杂鲁胺产生耐药性。这种谱系可塑性是由TP53和RB1功能丧失所促成，由重编程转录因子SOX2表达增加所介导，并且可通过恢复TP53和RB1功能或抑制SOX2表达来逆转。因此，肿瘤抑制基因的突变可产生细胞可塑性增加的状态，当受到抗雄激素治疗挑战时，这种状态会通过谱系转换促进耐药性。
