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The mechanisms of resistance to CDK4/6 inhibitors (CDK4/6i) in hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer (BC) are heterogeneous. We have previously identified a common DNA-hypomethylated pattern in Palbociclib-resistant (PDR) cell lines, but the impact of epigenomic alterations in driving resistance to this CDK4/6i in HR+/HER2- BC remains unknown. To investigate the role of epigenomic alterations in CDK4/6i-resistance, we profiled five HR+/HER2- BC PDR cell lines, along with their parental counterparts, by RNAseq, WES and Infinium Methylation EPIC arrays. Transcription, genomic and promoter DNA-methylation data were integrated to identify genes and pathways significantly modulated at the transcriptomic level either by DNA-methylation or by genomic alterations. LISA was used to predict potential transcriptional regulators of co-deregulated genes. As expected, in all PDR models we found a mild but significant positive correlation between differential gene expression and copy number status and a negative correlation between differential gene expression and DNA-methylation level at promoters. The overlap between differentially expressed genes and genes modulated by copy number and/or DNA methylation varied across all the PDR models, with a range of 0.35-15.8% of significantly overlapping genes. Functional enrichment analysis on genes with differential transcriptional and copy number status did not reveal co-deregulated pathways. Conversely, gene ontology analysis of differentially up-regulated and hypomethylated or down-regulated and hypermethylated genes, identified ER signaling as the only common co-deregulated pathway in 4/5 models. Moreover, among the top 20 transcription factors regulating the overexpressed and hypomethylated genes in PDR models, ER was the only common hit in 4/5 models. This integrated multi-omics analysis suggests that, among heterogeneous and model-specific mechanisms, modulation of ER signaling might be a common feature of resistance to CDK4/6i. At resistance, the methylation status of promoters could serve as an additional tool for assessing the modulation of the ER pathway.
Guarducci et al. (Wed,) studied this question.