Abstract 1798: Mechanisms of acquired resistance to palbociclib reveals pathways of response to abemaciclib
Authors: Navarro-Yepes Juliana , Kettner Nicole M. , Bui Tuyen , Raghavendra Akshara S. , Rao Xiayu , Wang Jing , Sahin Aysegul , Damodaran Senthil , Tripathy Debasish , Hunt Kelly K. , Keyomarsi Khandan 
Published: June 2022

Abstract
Background: CDK4/6 inhibitors (CDK4/6i) plus endocrine therapy (ET) delay progression and improve survival in patients with hormone receptor positive (HR+), HER2 negative metastatic breast cancer (MBC). However, most patients develop resistance to CDK4/6i leading to disease progression, thus new therapies to overcome resistance are needed. CDK4/6i [palbociclib (palbo), ribociclib (ribo), and abemaciclib (abema)] have the same nominal targets but vary in their target specificity and are pharmacologically distinct. Clinical benefit was observed in patients treated with abema after progression on a prior CDK4/6i suggesting that palbo/ribo refractory tumors retain abema sensitivity. We hypothesize that mechanisms driving acquired resistance to palbo and abema are distinct, and palbo-resistant models may be responsive to abema.
Models: 1) MCF-7 and T47D palbo and abema resistant cells, 2) patient derived xenografts (PDX) established from patients who progressed on ET alone (ET-resistant) or palbo + ET (palbo-resistant), 3) organoids derived from the palbo-resistant PDX, and 4) a HR+/HER2- MBC patient cohort who received abema after progression on palbo therapy.
Results: RNA-sequencing and proteomic analysis revealed that palbo and abema resistant cells exhibit more than 30 differentially altered pathways. EMT, IL6/STAT3, and CSC pathways were upregulated only in palbo-resistant cells, but not in abema-resistant cells. Palbo-resistant cells also showed upregulation of G2M/Mitotic spindle and downregulation of ER pathways, whereas abema-resistant cells displayed downregulation of G2M/Mitotic spindle and upregulation of ER pathways. Mechanistic analysis revealed that palbo-resistant cells are responsive to abema with a delay in doubling time and a reduction of the proliferation marker pHH3. Further, cells accumulated in the G2M-phase with concomitant high phospho-(Y15)-CDK1 and cyclin B levels. Organoid cultures generated from palbo-resistant PDX were sensitive to abema. Likewise, abema significantly delayed the tumor growth of palbo-resistant PDX, correlating in vivo with ex vivo treatments. Moreover, we assessed response to abema after progression on palbo in the ET-resistant PDX model (CDK4/6 sensitive) demonstrating a continued survival benefit from abema treatment compared to palbo. Clinical outcome analyses of a MBC patient cohort treated with abema following prior CDK4/6i showed a median progression free survival (PFS) of 6.3 months in those treated sequentially vs a PFS of 4.0 months in non-sequential treated patients.
Conclusion: Differential mechanism underlying palbo and abema acquired resistance can be exploited to overcome CDK4/6i resistance. These results provide rationale for clinical trials evaluating the benefit of abema treatment following progression on a prior CDK4/6i.
Citation Format: Juliana Navarro-Yepes, Nicole M. Kettner, Tuyen Bui, Akshara S. Raghavendra, Xiayu Rao, Jing Wang, Aysegul Sahin, Senthil Damodaran, Debasish Tripathy, Kelly K. Hunt, Khandan Keyomarsi. Mechanisms of acquired resistance to palbociclib reveals pathways of response to abemaciclib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1798.