Department of Medicine, School of Medicine, University of Louisville, Louisville, KY, 40202, USA.
College of Medicine, University of Kentucky, Lexington, KY, 40506, USA.
Breast Cancer Res Treat. 2021 Apr;186(3):677-686. doi: 10.1007/s10549-021-06127-5. Epub 2021 Feb 18.
The management of triple-negative breast cancer (TNBC) remains a significant clinical challenge due to the lack of effective targeted therapies. Inhibitors of the cyclin-dependent kinases 4 and 6 (CDK4/6) are emerging as promising therapeutic agents against TNBC; however, cells can rapidly acquire resistance through multiple mechanisms that are yet to be identified. Therefore, determining the mechanisms underlying resistance to CDK4/6 inhibition is crucial to develop combination therapies that can extend the efficacy of the CDK4/6 inhibitors or delay resistance. This study aims to identify differentially expressed genes (DEG) associated with acquired resistance to palbociclib in ER- breast cancer cells.
We performed next-generation transcriptomic sequencing (RNA-seq) and pathway analysis in ER- MDA-MB-231 palbociclib-sensitive (231/pS) and palbociclib-resistant (231/pR) cells.
We identified 2247 up-regulated and 1427 down-regulated transcripts in 231/pR compared to 231/pS cells. DEGs were subjected to functional analysis using Gene Ontology (GO) and the KEGG database which identified many transduction pathways associated with breast cancer, including the PI3K/AKT, PTEN and mTOR pathways. Additionally, Ingenuity Pathway Analysis (IPA) revealed that resistance to palbociclib is closely associated with altered cholesterol and fatty acid biosynthesis suggesting that resistance to palbociclib may be dependent on lipid metabolic reprograming.
This study provides evidence that lipid metabolism is altered in TNBC with acquired resistance to palbociclib. Further studies are needed to determine if the observed lipid metabolic rewiring can be exploited to overcome therapy resistance in TNBC.
由于缺乏有效的靶向治疗方法，三阴性乳腺癌（TNBC）的治疗仍然是一个重大的临床挑战。细胞周期蛋白依赖性激酶 4 和 6（CDK4/6）抑制剂是针对 TNBC 的有前途的治疗药物；然而，细胞可以通过多种尚未确定的机制迅速获得耐药性。因此，确定对 CDK4/6 抑制产生耐药性的机制对于开发联合疗法以延长 CDK4/6 抑制剂的疗效或延迟耐药性至关重要。本研究旨在鉴定与 ER- 乳腺癌细胞对 palbociclib 获得性耐药相关的差异表达基因（DEG）。
我们对 ER- MDA-MB-231 palbociclib 敏感（231/pS）和 palbociclib 耐药（231/pR）细胞进行了下一代转录组测序（RNA-seq）和通路分析。
与 231/pS 细胞相比，231/pR 细胞中上调了 2247 个基因，下调了 1427 个基因。使用基因本体论（GO）和 KEGG 数据库对 DEGs 进行功能分析，鉴定出许多与乳腺癌相关的转导途径，包括 PI3K/AKT、PTEN 和 mTOR 途径。此外，Ingenuity Pathway Analysis（IPA）显示，对 palbociclib 的耐药性与胆固醇和脂肪酸生物合成的改变密切相关，表明对 palbociclib 的耐药性可能依赖于脂质代谢的重新编程。
本研究提供的证据表明，TNBC 对 palbociclib 获得性耐药时，脂质代谢发生改变。需要进一步研究以确定观察到的脂质代谢重编程是否可以用于克服 TNBC 的治疗耐药性。
