Differential gene expression analysis of palbociclib-resistant TNBC via RNA-seq

• Published in: Breast cancer research and treatment Vol. 186; no. 3; pp. 677 - 686
• Main Authors: Lanceta, Lilibeth, Lypova, Nadiia, O’Neill, Conor, Li, Xiaohong, Rouchka, Eric, Chesney, Jason, Imbert-Fernandez, Yoannis
• Format: Journal Article
• Language: English
• Published: New York Springer US 01-04-2021; Springer; Springer Nature B.V
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Analysis; Breast cancer; Cancer research; Cholesterol; Cyclin-dependent kinase 4; Cyclin-dependent kinases; Fatty acids; Gene expression; Genes; Genetic aspects; Health aspects; Kinases; Lipid metabolism; Lipids; Medical colleges; Medicine; Medicine & Public Health; Metabolism; Neurophysiology; Oncology; Physiological aspects; Preclinical Study; PTEN protein; RNA; TOR protein; Transcriptomics; Metabolism reprogramming; Therapy resistance; TNBC; Palbociclib; CDK4/6 inhibitors
• ISSN: 0167-6806; 1573-7217
• DOI: 10.1007/s10549-021-06127-5

Purpose
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.
Methods
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.
Results
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.
Conclusion
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.