Abstract PO3-15-03: Abemaciclib is effective in palbociclib resistant estrogen receptor positive breast cancers
Authors: Navarro-Yepes Juliana , Kettner Nicole , Rao Xiayu , Bui Tuyen , Bishop Cassandra , Wingate Hannah , Raghavendra Akshara Singareeka , Wang Yan , Wang Jing , Sahin Aysegul , Meric-Bernstam Funda , Hunt Kelly , Damodaran Senthil , Tripathy Debu , Keyomarsi Khandan 
Published: May 2024

Abstract
Introduction: Hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (Her2)-negative breast cancer constitutes the majority of breast cancer cases and is commonly treated with endocrine therapy (ET). However, resistance to ET is a significant clinical challenge in metastatic breast cancer (MBC). The addition of cyclin-dependent kinase 4/6 inhibitors (CDK4/6is), such as palbociclib, ribociclib, and abemaciclib, to ET has shown promise in delaying disease progression. Nonetheless, resistance to CDK4/6is remains a concern, necessitating the exploration of alternative treatment strategies. This study aims to investigate the distinct mechanisms of resistance between palbociclib and abemaciclib and evaluate the sequential use or targeting of differentially altered pathways to delay disease progression in HR-positive/HER2-negative tumors.
Models: In vitro models of palbociclib-resistant (PR) and abemaciclib-resistant (AR) cell lines were generated to elucidate the pathways leading to resistance. Patient-derived xenografts (PDX) and ex vivo PDX-derived organoids (PDxOs) from MBC patients who experienced progression on CDK4/6is were also employed.
Results: PR and AR cells exhibited unique transcriptomic and proteomic profiles, with 14 similarly and 30 differentially altered pathways identified between PR and AR in vitro models. Epithelial-mesenchymal transition (EMT) and hypoxia were enriched in PR cells but not in AR cells, while oxidative phosphorylation (OXPHOS) and reactive oxygen species pathways were enriched in AR cells. Consequently, PR cells responded to abemaciclib, whereas AR cells showed sensitivity to OXPHOS inhibitors. Genomic alterations were heterogeneous and did not consistently predict palbociclib response. Furthermore, the use of organoids and PDX models confirmed that tumors with high expression of G2/M pathway genes remained responsive to abemaciclib. Clinical data from a cohort of patients with HR-positive/HER2-negative MBC demonstrated that sequential treatment with palbociclib and abemaciclib resulted in significantly longer overall survival (42.7 months versus 17.3 months) compared to non-sequential therapy.
Conclusion: Transcriptomic and proteomic analyses revealed distinct pathways in PR and AR models, suggesting that patients with enrichment of the G2/M pathway are likely to benefit from abemaciclib following palbociclib resistance, whereas those with enrichment of the OXPHOS pathway are most likely to be refractory. These findings support the need for prospective trials to evaluate the clinical benefit of abemaciclib after progression on a prior CDK4/6i regimen.
Citation Format: Juliana Navarro-Yepes, Nicole Kettner, Xiayu Rao, Tuyen Bui, Cassandra Bishop, Hannah Wingate, Akshara Singareeka Raghavendra, Yan Wang, Jing Wang, Aysegul Sahin, Funda Meric-Bernstam, Kelly Hunt, Senthil Damodaran, Debu Tripathy, Khandan Keyomarsi. Abemaciclib is effective in palbociclib resistant estrogen receptor positive breast cancers [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-15-03.