肿瘤经常含有同基因但表观遗传学不同的多能细胞亚群，具有高肿瘤启动潜力，通常称为癌症干细胞样细胞（CSLC）。这些可以表现出对标准化疗的优先耐药性。单细胞分析可以帮助阐明负责控制这些细胞转录状态的主调节蛋白 (MR)，从而揭示可通过联合疗法利用的互补依赖性。使用临床相关药物的扰动图谱对 7 名转移性乳腺癌患者的单细胞 RNA 测序图谱进行询问，确定了预测可逆转控制化疗耐药 CSLC 转录状态的 MR 蛋白活性的药物，然后通过 CROP-seq 测定进行验证。顶级药物驱虫药阿苯达唑在体内消除了该亚群，且没有明显的细胞毒性。此外，阿苯达唑和紫杉醇（一种常用的化疗药物）的连续周期在来自 TNBC 患者的患者来源的异种移植物（PDX）中显示出显着的协同作用，这表明基于网络的方法可以帮助开发针对互补亚群的基于机制的组合疗法。正如一项关于转移性乳腺癌的研究所示，基于基因的方法可以开发针对互补亚群的有效组合疗法。通过分析 scRNA-seq 数据并使用临床相关药物，研究人员鉴定并消除了化疗耐药性癌症干细胞样细胞，从而增强了标准化疗的疗效。

Tumors frequently harbor isogenic yet epigenetically distinct subpopulations of multi-potent cells with high tumor-initiating potential-often called Cancer Stem-Like Cells (CSLCs). These can display preferential resistance to standard-of-care chemotherapy. Single-cell analyses can help elucidate Master Regulator (MR) proteins responsible for governing the transcriptional state of these cells, thus revealing complementary dependencies that may be leveraged via combination therapy. Interrogation of single-cell RNA sequencing profiles from seven metastatic breast cancer patients, using perturbational profiles of clinically relevant drugs, identified drugs predicted to invert the activity of MR proteins governing the transcriptional state of chemoresistant CSLCs, which were then validated by CROP-seq assays. The top drug, the anthelmintic albendazole, depleted this subpopulation in vivo without noticeable cytotoxicity. Moreover, sequential cycles of albendazole and paclitaxel-a commonly used chemotherapeutic -displayed significant synergy in a patient-derived xenograft (PDX) from a TNBC patient, suggesting that network-based approaches can help develop mechanism-based combinatorial therapies targeting complementary subpopulations.Network-based approaches, as shown in a study on metastatic breast cancer, can develop effective combinatorial therapies targeting complementary subpopulations. By analyzing scRNA-seq data and using clinically relevant drugs, researchers identified and depleted chemoresistant Cancer Stem-Like Cells, enhancing the efficacy of standard chemotherapies.