Real-world clinical multi-omics analyses reveal bifurcation of ER-independent and ER-dependent drug resistance to CDK4/6 inhibitors
Abstract To better understand drug resistance mechanisms to CDK4/6 inhibitors and inform precision medicine, we analyze real-world multi-omics data from 400 HR+/HER2- metastatic breast cancer patients treated with CDK4/6 inhibitors plus endocrine therapies, including 200 pre-treatment and 227 post-p...
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| Format: | Article |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-55914-x |
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| author | Zhengyan Kan Ji Wen Vinicius Bonato Jennifer Webster Wenjing Yang Vladimir Ivanov Kimberly Hyunjung Kim Whijae Roh Chaoting Liu Xinmeng Jasmine Mu Jennifer Lapira-Miller Jon Oyer Todd VanArsdale Paul A. Rejto Jadwiga Bienkowska |
| author_facet | Zhengyan Kan Ji Wen Vinicius Bonato Jennifer Webster Wenjing Yang Vladimir Ivanov Kimberly Hyunjung Kim Whijae Roh Chaoting Liu Xinmeng Jasmine Mu Jennifer Lapira-Miller Jon Oyer Todd VanArsdale Paul A. Rejto Jadwiga Bienkowska |
| author_sort | Zhengyan Kan |
| collection | DOAJ |
| description | Abstract To better understand drug resistance mechanisms to CDK4/6 inhibitors and inform precision medicine, we analyze real-world multi-omics data from 400 HR+/HER2- metastatic breast cancer patients treated with CDK4/6 inhibitors plus endocrine therapies, including 200 pre-treatment and 227 post-progression samples. The prevalences of ESR1 and RB1 alterations significantly increase in post-progression samples. Integrative clustering analysis identifies three subgroups harboring different resistance mechanisms: ER driven, ER co-driven and ER independent. The ER independent subgroup, growing from 5% pre-treatment to 21% post-progression, is characterized by down-regulated estrogen signaling and enrichment of resistance markers including TP53 mutations, CCNE1 over-expression and Her2/Basal subtypes. Trajectory inference analyses identify a pseudotime variable strongly correlated with ER independence and disease progression; and revealed bifurcated evolutionary trajectories for ER-independent vs. ER-dependent drug resistance mechanisms. Machine learning models predict therapeutic dependency on ESR1 and CDK4 among ER-dependent tumors and CDK2 dependency among ER-independent tumors, confirmed by experimental validation. |
| format | Article |
| id | doaj-art-a386a891e600428c99ba0e1e1867b722 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-a386a891e600428c99ba0e1e1867b7222025-01-26T12:42:53ZengNature PortfolioNature Communications2041-17232025-01-0116111910.1038/s41467-025-55914-xReal-world clinical multi-omics analyses reveal bifurcation of ER-independent and ER-dependent drug resistance to CDK4/6 inhibitorsZhengyan Kan0Ji Wen1Vinicius Bonato2Jennifer Webster3Wenjing Yang4Vladimir Ivanov5Kimberly Hyunjung Kim6Whijae Roh7Chaoting Liu8Xinmeng Jasmine Mu9Jennifer Lapira-Miller10Jon Oyer11Todd VanArsdale12Paul A. Rejto13Jadwiga Bienkowska14Oncology Research & Development, Pfizer Inc.Oncology Research & Development, Pfizer Inc.Biostatistics, Pfizer Inc.Real World Evidence, Pfizer Inc.Oncology Research & Development, Pfizer Inc.Global Biometrics & Data Management, Pfizer Inc.Oncology Research & Development, Pfizer Inc.Oncology Research & Development, Pfizer Inc.Oncology Research & Development, Pfizer Inc.Oncology Research & Development, Pfizer Inc.Oncology Research & Development, Pfizer Inc.Oncology Research & Development, Pfizer Inc.Oncology Research & Development, Pfizer Inc.Oncology Research & Development, Pfizer Inc.Oncology Research & Development, Pfizer Inc.Abstract To better understand drug resistance mechanisms to CDK4/6 inhibitors and inform precision medicine, we analyze real-world multi-omics data from 400 HR+/HER2- metastatic breast cancer patients treated with CDK4/6 inhibitors plus endocrine therapies, including 200 pre-treatment and 227 post-progression samples. The prevalences of ESR1 and RB1 alterations significantly increase in post-progression samples. Integrative clustering analysis identifies three subgroups harboring different resistance mechanisms: ER driven, ER co-driven and ER independent. The ER independent subgroup, growing from 5% pre-treatment to 21% post-progression, is characterized by down-regulated estrogen signaling and enrichment of resistance markers including TP53 mutations, CCNE1 over-expression and Her2/Basal subtypes. Trajectory inference analyses identify a pseudotime variable strongly correlated with ER independence and disease progression; and revealed bifurcated evolutionary trajectories for ER-independent vs. ER-dependent drug resistance mechanisms. Machine learning models predict therapeutic dependency on ESR1 and CDK4 among ER-dependent tumors and CDK2 dependency among ER-independent tumors, confirmed by experimental validation.https://doi.org/10.1038/s41467-025-55914-x |
| spellingShingle | Zhengyan Kan Ji Wen Vinicius Bonato Jennifer Webster Wenjing Yang Vladimir Ivanov Kimberly Hyunjung Kim Whijae Roh Chaoting Liu Xinmeng Jasmine Mu Jennifer Lapira-Miller Jon Oyer Todd VanArsdale Paul A. Rejto Jadwiga Bienkowska Real-world clinical multi-omics analyses reveal bifurcation of ER-independent and ER-dependent drug resistance to CDK4/6 inhibitors Nature Communications |
| title | Real-world clinical multi-omics analyses reveal bifurcation of ER-independent and ER-dependent drug resistance to CDK4/6 inhibitors |
| title_full | Real-world clinical multi-omics analyses reveal bifurcation of ER-independent and ER-dependent drug resistance to CDK4/6 inhibitors |
| title_fullStr | Real-world clinical multi-omics analyses reveal bifurcation of ER-independent and ER-dependent drug resistance to CDK4/6 inhibitors |
| title_full_unstemmed | Real-world clinical multi-omics analyses reveal bifurcation of ER-independent and ER-dependent drug resistance to CDK4/6 inhibitors |
| title_short | Real-world clinical multi-omics analyses reveal bifurcation of ER-independent and ER-dependent drug resistance to CDK4/6 inhibitors |
| title_sort | real world clinical multi omics analyses reveal bifurcation of er independent and er dependent drug resistance to cdk4 6 inhibitors |
| url | https://doi.org/10.1038/s41467-025-55914-x |
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