Abstract 45P
Background
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.
Methods
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.
Results
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.
Conclusions
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.
Legal entity responsible for the study
The authors.
Funding
"Fondazione AIRC per la Ricerca sul Cancro" and "Fondazione Sandro Pitigliani per la lotta contro i tumor-ONLUS".
Disclosure
L. Biganzoli: Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi Sankyo, Eisai, Pfizer, Gilead, Sanofi, Seattle Genetics, Exact Sciences, Amgen, Boehringer-Ingelheim, Pierre Fabre, Menarini; Financial Interests, Personal, Invited Speaker: Lilly, Novartis, Roche; Financial Interests, Institutional, Research Grant: Celgene, Genomic Health, Novartis; Non-Financial Interests, Member of Board of Directors: SIOG. D.W. Cescon: Financial Interests, Personal, Advisory Role: AstraZeneca, Daiichi Sankyo, Eisai, Gilead, GSK, Inflex, Inivata/NeoGenomics, Lilly, Merck, Novartis, Pfizer, Roche, Saga; Financial Interests, Institutional, Funding: AstraZeneca, Guardant Health, Gilead, GSK, Inivata/NeoGenomics, Knight, Merck, Pfizer, ProteinQure, Roche; Financial Interests, Personal, Advisory Board: AstraZeneca, Merck, GSK; Financial Interests, Personal, Other, a holds a patent (US62/675,228) for methods of treating cancers characterized by a high expression level of spindle and kinetochore associated complex subunit 3 (ska3) gene: David Cescon. R. Schiff: Financial Interests, Institutional, Funding: AstraZeneca, GSK, Puma, Biotechnology Inc., Gilead Sciences; Financial Interests, Personal, Invited Speaker: BinaytaraFoundation, Dava Oncology LP; Financial Interests, Personal, Sponsor/Funding: BinaytaraFoundation, Dava Oncology LP; Financial Interests, Personal, Advisory Board: Eli Lilly Daiichi Sankyo, MacroGenics; Financial Interests, Personal, Royalties: UpToDate; Financial Interests, Personal and Institutional, Other, Patent # PCT/US21/70543 (Methods for breast cancer treatment and prediction of therapeutic response: Baylor College of Medicine’s ; Financial Interests, Personal, Member, member of the SABCS (Breast cancer symposium) Faculty/Planning Committees: SABCS. M. Benelli: Financial Interests, Personal, Other, Personal fees for consultancy on bioinformatics analyses: Novartis. L. Malorni: Financial Interests, Personal, Invited Speaker: Pfizer, Lilly, Novartis, Menarini, Novartis; Financial Interests, Personal, Advisory Board: Lilly, Seagen, Roche, Menarini, Pfizer; Financial Interests, Institutional, Research Grant: Pfizer, Novartis; Non-Financial Interests, Institutional, Product Samples: Biovica International; Other, Principal investigator in one clinical trialco-Principal Investigator in one clinical trial: International Breast Cancer Study Group (IBCSG). All other authors have declared no conflicts of interest.