Multi-Omics Investigation of Innate Navitoclax Resistance in Triple-Negative Breast Cancer Cells.
Multi-Omics Investigation of Innate Navitoclax Resistance in Triple-Negative Breast Cancer Cells.
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DOI：
10.3390/cancers12092551
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发表时间：
2020-09-08
期刊：
影响因子：
5.2
通讯作者：
Gunasekharan V
中科院分区：
文献类型：
--
作者：
Marczyk M;Patwardhan GA;Zhao J;Qu R;Li X;Wali VB;Gupta AK;Pillai MM;Kluger Y;Yan Q;Hatzis C;Pusztai L;Gunasekharan V
三阴性乳腺癌是一种治疗选择有限的疾病，在所有乳腺癌亚型中预后最差，因此对新的有效疗法的需求很高。我们最近发现navitoclax与其他药物在治疗三阴性乳腺癌细胞中表现出协同抗增殖和凋亡活性，但对治疗的抵抗仍然是一个限制因素。因此，我们在体外研究了navitoclax处理对转录组、基因组和表观基因组的影响，以更好地了解耐药的产生过程。我们发现并验证了多个以前未知的耐药标记，这些标记可以帮助在未来涉及navitoclax的临床试验中选择患者。癌细胞采用多种防御机制对抗药物诱导的细胞死亡。研究治疗前后癌细胞的多组学景观可以揭示耐药机制并为新的治疗策略提供信息。我们评估了navitoclax（一种BCL2家族抑制剂）对MDA-MB-231三阴性乳腺癌（TNBC）细胞转录组、甲基组、染色质结构和拷贝数变化的影响。在治疗前、暴露72小时和治疗后10天无药恢复后分别取样细胞。我们观察到应激反应基因的表达发生了短暂的变化，并伴随着染色质可及性的相应变化。恢复期后，这些变化大多恢复到基线水平。我们还检测到甲基化状态和基因组结构的持续变化，这表明细胞群体组成发生了永久性变化。通过单细胞分析，我们确定了2350个基因在navitoclax耐药细胞中显著上调，并获得了一个18个基因的navitoclax耐药特征。我们在体外评估了另外四种TNBC细胞系的navitoclax反应预测功能，并在251种不同药物治疗的619种细胞系中进行了计算机模拟。我们在两个实验中都观察到药物特异性的预测值，这表明这一特征可以帮助指导涉及navitoclax的临床生物标志物研究。
Triple negative breast cancer is a disease with limited treatment options and the poorest outcome across all breast cancer subtypes, thus the need for new effective therapies is high. We recently found that navitoclax displays synergistic anti-proliferative and apoptotic activities with other drugs in treatment of triple negative breast cancer cells, but the resistance to treatment is still a limiting factor. Therefore, we investigated the effects of navitoclax treatment on the transcriptome, genome and epigenome in vitro to better understand the process of developing resistance. We discovered and validated a list of multiple, previously unknown markers of drug resistance that can help in patient selection in future clinical trials involving navitoclax. Cancer cells employ various defense mechanisms against drug-induced cell death. Investigating multi-omics landscapes of cancer cells before and after treatment can reveal resistance mechanisms and inform new therapeutic strategies. We assessed the effects of navitoclax, a BCL2 family inhibitor, on the transcriptome, methylome, chromatin structure, and copy number variations of MDA-MB-231 triple-negative breast cancer (TNBC) cells. Cells were sampled before treatment, at 72 h of exposure, and after 10-day drug-free recovery from treatment. We observed transient alterations in the expression of stress response genes that were accompanied by corresponding changes in chromatin accessibility. Most of these changes returned to baseline after the recovery period. We also detected lasting alterations in methylation states and genome structure that suggest permanent changes in cell population composition. Using single-cell analyses, we identified 2350 genes significantly upregulated in navitoclax-resistant cells and derived an 18-gene navitoclax resistance signature. We assessed the navitoclax-response-predictive function of this signature in four additional TNBC cell lines in vitro and in silico in 619 cell lines treated with 251 different drugs. We observed a drug-specific predictive value in both experiments, suggesting that this signature could help guiding clinical biomarker studies involving navitoclax.
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