Real-world clinical multi-omics analyses reveal bifurcation of ER-independent and ER-dependent drug resistance to CDK4/6 inhibitors

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 and Jadwiga Bienkowska ()
Additional contact information
Zhengyan Kan: Pfizer Inc.
Ji Wen: Pfizer Inc.
Vinicius Bonato: Pfizer Inc.
Jennifer Webster: Pfizer Inc.
Wenjing Yang: Pfizer Inc.
Vladimir Ivanov: Pfizer Inc.
Kimberly Hyunjung Kim: Pfizer Inc.
Whijae Roh: Pfizer Inc.
Chaoting Liu: Pfizer Inc.
Xinmeng Jasmine Mu: Pfizer Inc.
Jennifer Lapira-Miller: Pfizer Inc.
Jon Oyer: Pfizer Inc.
Todd VanArsdale: Pfizer Inc.
Paul A. Rejto: Pfizer Inc.
Jadwiga Bienkowska: Pfizer Inc.

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-55914-x

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