Lamichhane Astha, Shahi Thakuri Pradip, Singh Sunil, Rafsanjani Nejad Pouria, Heiss Jacob, Luker Gary D, Tavana Hossein
Department of Biomedical Engineering, The University of Akron, Akron, Ohio 44325, United States.
Department of Radiology, Microbiology and Immunology, Biomedical Engineering, University of Michigan, Ann Arbor, Michigan 48105, United States.
ACS Pharmacol Transl Sci. 2022 Aug 25;5(9):724-734. doi: 10.1021/acsptsci.1c00257. eCollection 2022 Sep 9.
Drug resistance is a leading cause for the failure of cancer treatments. Plasticity of cancer cells to acquire stem cell-like properties enables them to escape drug toxicity through different adaptive mechanisms. Eliminating cancer stem cells (CSCs) can potentially improve treatment outcomes for patients. To determine the role of CSCs in resistance of colorectal cancer cells to targeted therapies and identify treatment strategies, we treated spheroids of BRAF and KRAS colorectal cancer cells with inhibitors of the mitogen-activated protein kinase pathway and studied resistance mechanisms through gene and protein expression analyses. We found that treatments activated several oncogenic pathways and expression of CSC markers CD166 and ALDH1A3. We identified a specific combination treatment using trametinib and mithramycin A to simultaneously inhibit the CSC phenotype and activities of several pathways in cancer cells. This study demonstrates the feasibility of therapeutic targeting of CSCs as a strategy to block tumorigenic activities of cancer cells.
耐药性是癌症治疗失败的主要原因。癌细胞获得干细胞样特性的可塑性使它们能够通过不同的适应性机制逃避药物毒性。消除癌症干细胞（CSCs）可能会改善患者的治疗效果。为了确定CSCs在大肠癌细胞对靶向治疗的耐药性中的作用并确定治疗策略，我们用丝裂原活化蛋白激酶途径抑制剂处理BRAF和KRAS大肠癌细胞的球体，并通过基因和蛋白质表达分析研究耐药机制。我们发现这些处理激活了几种致癌途径以及癌症干细胞标志物CD166和ALDH1A3的表达。我们确定了一种使用曲美替尼和光神霉素A的联合治疗方案，以同时抑制癌细胞中的癌症干细胞表型和几种途径的活性。这项研究证明了将癌症干细胞作为一种阻断癌细胞致瘤活性的策略进行治疗靶向的可行性。
