Nature Communications ( IF 16.6 ) Pub Date : 2020-07-03 , DOI: 10.1038/s41467-020-17090-y Rotem Ben-Hamo 1, 2 , Adi Jacob Berger 1 , Nancy Gavert 1 , Mendy Miller 2 , Guy Pines 3 , Roni Oren 4 , Eli Pikarsky 5 , Cyril H Benes 6, 7 , Tzahi Neuman 5 , Yaara Zwang 1 , Sol Efroni 6 , Gad Getz 2, 7, 8, 9 , Ravid Straussman 1
Identifying robust, patient-specific, and predictive biomarkers presents a major obstacle in precision oncology. To optimize patient-specific therapeutic strategies, here we couple pathway knowledge with large-scale drug sensitivity, RNAi, and CRISPR-Cas9 screening data from 460 cell lines. Pathway activity levels are found to be strong predictive biomarkers for the essentiality of 15 proteins, including the essentiality of MAD2L1 in breast cancer patients with high BRCA-pathway activity. We also find strong predictive biomarkers for the sensitivity to 31 compounds, including BCL2 and microtubule inhibitors (MTIs). Lastly, we show that Bcl-xL inhibition can modulate the activity of a predictive biomarker pathway and re-sensitize lung cancer cells and tumors to MTI therapy. Overall, our results support the use of pathways in helping to achieve the goal of precision medicine by uncovering dozens of predictive biomarkers.
中文翻译:
基于途径水平的生物标志物预测并影响对癌症治疗的反应。
鉴定健壮的,针对患者的,可预测的生物标志物是精密肿瘤学的主要障碍。为了优化针对患者的治疗策略,此处我们将途径知识与来自460个细胞系的大规模药物敏感性,RNAi和CRISPR-Cas9筛选数据结合在一起。发现通路活性水平是15种蛋白质必要性的强预测生物标志物,包括具有高BRCA通路活性的乳腺癌患者中MAD2L1的必需性。我们还发现了对31种化合物(包括BCL2和微管抑制剂(MTIs))的敏感性的强大预测性生物标记。最后,我们表明Bcl-xL抑制可以调节预测性生物标志物通路的活性,并使肺癌细胞和肿瘤对MTI治疗重新敏感。总体,