Division of Molecular Oncology, ICMR-National Institute of Cancer Prevention and Research, I-7, Sector-39, Noida, Uttar Pradesh, 201301, India.
Department of Research, Sir Ganga Ram Hospital, 110060, New Delhi, India.
Mol Omics. 2023 Jun 12;19(5):404-417. doi: 10.1039/d2mo00285j.
Abemaciclib (Ab) and palbociclib (Pb) are CDK4/6 inhibitors used to cure advanced breast cancer (BC). However, acquired resistance is a major challenge. The molecular mechanisms and signature proteins of therapy resistance for Ab and Pb drugs need to be explored. Here we developed resistant cells for Ab and Pb drugs in MCF-7 cell lines and explored the mechanisms and signature proteins of therapy resistance in BC. Proteome profiling was performed using the label-free proteome-orbitrap-fusion-MS-MS technique. Gene ontology (GO)-terms, KEGG pathways and network analysis were performed for the proteome data. Drug-resistant cells showed increased drug tolerance, enhanced colony formation potential and an increased gap-healing tendency for the respective drug. Up-regulation of survival genes (BCL-2 and MCL-1) and down-regulation of apoptosis inducers were observed. Drug-resistance markers (MDR-1 and ABCG2 (BCRP)) along with ESR-1, CDK4, CDK6, and cyclin-D1 genes were up-regulated in resistant cells. A total of 237 and 239 proteins were found to be differentially expressed in the Ab and Pb-resistant cells, respectively. Down-regulated proteins induce apoptosis signalling and nucleotide metabolisms and restrict EGFR signalling; however, up-regulated proteins induce Erk, wnt-β-catenin, VEGFR-PI3K-AKT, glucose transportation, and hypoxia signalling pathways and regulate hydrogen peroxide signalling pathways. The panel of identified proteins associated with these pathways might have characteristics of molecular signature and new drug targets for overcoming drug resistance in breast cancer.
阿贝西利（Ab）和帕博西利（Pb）是用于治疗晚期乳腺癌（BC）的 CDK4/6 抑制剂。然而，获得性耐药是一个主要挑战。需要探索 Ab 和 Pb 药物耐药的分子机制和特征蛋白。在这里，我们在 MCF-7 细胞系中开发了 Ab 和 Pb 药物的耐药细胞，并探索了 BC 中治疗耐药的机制和特征蛋白。使用无标记蛋白质组-轨道融合-MS-MS 技术进行蛋白质组谱分析。对蛋白质组数据进行了基因本体（GO）术语、KEGG 通路和网络分析。耐药细胞表现出增加的药物耐受性、增强的集落形成潜力和各自药物的间隙愈合趋势增加。观察到存活基因（BCL-2 和 MCL-1）的上调和凋亡诱导物的下调。耐药标志物（MDR-1 和 ABCG2（BCRP））以及 ESR-1、CDK4、CDK6 和 cyclin-D1 基因在耐药细胞中上调。在 Ab 和 Pb 耐药细胞中分别发现了 237 和 239 个差异表达的蛋白质。下调的蛋白质诱导细胞凋亡信号和核苷酸代谢，并限制 EGFR 信号；然而，上调的蛋白质诱导 Erk、wnt-β-catenin、VEGFR-PI3K-AKT、葡萄糖转运和缺氧信号通路，并调节过氧化氢信号通路。与这些通路相关的鉴定蛋白质组可能具有分子特征的特征和克服乳腺癌耐药性的新药物靶点。
