Pharmacologic profiling of patient-derived xenograft models of primary treatment-naïve triple-negative breast cancer.
Pharmacologic profiling of patient-derived xenograft models of primary treatment-naïve triple-negative breast cancer.
复制标题
DOI：
10.1038/s41598-020-74882-4
复制
发表时间：
2020-10-21
影响因子：
4.6
通讯作者：
Piwnica-Worms H
中科院分区：
文献类型：
--
作者：
Powell RT;Redwood A;Liu X;Guo L;Cai S;Zhou X;Tu Y;Zhang X;Qi Y;Jiang Y;Echeverria G;Feng N;Ma X;Giuliani V;Marszalek JR;Heffernan TP;Vellano CP;White JB;Stephan C;Davies PJ;Moulder S;Symmans WF;Chang JT;Piwnica-Worms H
三阴性乳腺癌 (TNBC) 占美国乳腺癌病例的 15-20%，缺乏针对性的治疗选择，并且与 40-80% 的复发风险相关。因此，确定未接受过治疗和耐药的 TNBC 的可行靶点是一项未得到满足的关键医疗需求。为了满足这一需求，我们对从 16 个未经治疗的原发性 TNBC 患者来源的异种移植模型中分离出的人类肿瘤细胞进行了高通量药物活力筛选。这些模型涵盖一系列 TNBC 亚型，并表现出多种假定的驱动突变，从而提供了反映 TNBC 的独特的源自患者、分子注释的药理学资源。我们确定了可治疗的靶点，包括驱动蛋白纺锤体蛋白（KSP）。 KSP 抑制剂通过独立于微管稳定性的机制靶向有丝分裂纺锤体，并在对作为当前 TNBC 护理标准一部分的微管抑制剂具有耐药性的模型中显示出疗效。我们还观察到 Prima-1Met 的亚型选择性，其在间充质亚型中表现出更高水平的功效。将药理学数据与基因组和转录组信息相结合，我们发现 Prima-1Met 活性与其典型靶标突变体 p53 无关，并且与谷胱甘肽代谢有更好的相关性，为该药物提供了另一种分子定义的生物标志物。
Triple-negative breast cancer (TNBC) accounts for 15–20% of breast cancer cases in the United States, lacks targeted therapeutic options, and is associated with a 40–80% risk of recurrence. Thus, identifying actionable targets in treatment-naïve and chemoresistant TNBC is a critical unmet medical need. To address this need, we performed high-throughput drug viability screens on human tumor cells isolated from 16 patient-derived xenograft models of treatment-naïve primary TNBC. The models span a range of TNBC subtypes and exhibit a diverse set of putative driver mutations, thus providing a unique patient-derived, molecularly annotated pharmacologic resource that is reflective of TNBC. We identified therapeutically actionable targets including kinesin spindle protein (KSP). The KSP inhibitor targets the mitotic spindle through mechanisms independent of microtubule stability and showed efficacy in models that were resistant to microtubule inhibitors used as part of the current standard of care for TNBC. We also observed subtype selectivity of Prima-1Met, which showed higher levels of efficacy in the mesenchymal subtype. Coupling pharmacologic data with genomic and transcriptomic information, we showed that Prima-1Met activity was independent of its canonical target, mutant p53, and was better associated with glutathione metabolism, providing an alternate molecularly defined biomarker for this drug.
登录
查看更多内容
影响因子：
82.9
作者：
Gao, Hui;Korn, Joshua M.;Sellers, William R.
通讯作者：
Sellers, William R.
影响因子：
2.7
作者：
Niyomnaitham, Suvimol;Parinyanitikul, Napa;Pithukpakorn, Manop
通讯作者：
Pithukpakorn, Manop
影响因子：
45.3
作者：
Liedtke, Cornelia;Mazouni, Chafika;Pusztai, Lajos
通讯作者：
Pusztai, Lajos
DOI：
10.1016/j.bbacli.2015.03.003
发表时间：
2015-06
期刊：
BBA clinical
影响因子：
--
作者：
O'Reilly EA;Gubbins L;Sharma S;Tully R;Guang MH;Weiner-Gorzel K;McCaffrey J;Harrison M;Furlong F;Kell M;McCann A
通讯作者：
McCann A
影响因子：
50.3
作者：
Lambert, Jeremy M. R.;Gorzov, Petr;Bykov, Vladimir J. N.
通讯作者：
Bykov, Vladimir J. N.