Abemaciclib Is Effective in Palbociclib-Resistant Hormone Receptor-Positive Metastatic Breast Cancers

Authors

Juliana Navarro-Yepes
Nicole M Kettner
Xiayu Rao
Cassandra Santaella Bishop
Tuyen N Bui
Hannah F Wingate
Akshara Singareeka Raghavendra
Yan Wang
Jing Wang
Aysegul A Sahin
Funda Meric-Bernstam
Kelly K Hunt
Senthil Damodaran
Debu Tripathy
Khandan Keyomarsi

Publication Date

10-2-2023

Journal

Cancer Research

Abstract

Cyclin-dependent kinases 4/6 inhibitor (CDK4/6i) plus endocrine therapy (ET) is standard of care for patients with hormone receptor (HR)-positive, HER2-negative metastatic breast cancer (MBC). However, resistance to CDK4/6is plus ET remains a clinical problem with limited therapeutic options following disease progression. Different CDK4/6is might have distinct mechanisms of resistance, and therefore using them sequentially or targeting their differentially altered pathways could delay disease progression. To understand pathways leading to resistance to the CDK4/6is palbociclib and abemaciclib, we generated multiple in vitro models of palbociclib-resistant (PR) and abemaciclib-resistant (AR) cell lines as well as in vivo patient-derived xenografts (PDX) and ex vivo PDX-derived organoids (PDxO) from patients who progressed on CDK4/6i. PR and AR breast cancer cells exhibited distinct transcriptomic and proteomic profiles that sensitized them to different classes of inhibitors; PR cells upregulated G2-M pathways and responded to abemaciclib, while AR cells upregulated mediators of the oxidative phosphorylation pathway (OXPHOS) and responded to OXPHOS inhibitors. PDX and organoid models derived from patients with PR breast cancer remained responsive to abemaciclib. Resistance to palbociclib while maintaining sensitivity to abemaciclib was associated with pathway-specific transcriptional activity but was not associated with any individual genetic alterations. Finally, data from a cohort of 52 patients indicated that patients with HR-positive/HER2-negative MBC who progressed on palbociclib-containing regimens can exhibit a meaningful overall clinical benefit from abemaciclib-based therapy when administered after palbociclib. These findings provide the rationale for clinical trials evaluating the benefit of abemaciclib treatment following progression on a prior CDK4/6i.

Keywords

Animals, Humans, Female, Breast Neoplasms, Proteomics, Disease Models, Animal, Disease Progression, Cyclins, Cyclin-Dependent Kinase 4, Protein Kinase Inhibitors, Cyclin-Dependent Kinase 6, Antineoplastic Combined Chemotherapy Protocols

Comments

Supplementary Materials

PMID: 37384539