High levels of interferon-response gene signatures are associated with de novo and acquired resistance to CDK4/6 inhibitors in ER plus breast cancer

Background: The CDK4/6 inhibitors (i) palbociclib (Palbo), ribociclib, and abemaciclib remarkably improved the outcome of patients with metastatic ER+/HER2- breast cancer (BC) and are now under clinical investigation in early BC. Despite high efficacy, de novo and acquired resistance to CDK4/6i is common. Elucidating the molecular basis for sensitivity and resistance to CDK4/6i is crucial to identify predictive biomarkers and novel therapeutic targets to improve patient outcome. Materials and Methods: MCF7, T47D and ZR75-1 parental (P) BC cells and their derivatives made resistant to tamoxifen, estrogen deprivation (EDR), or fulvestrant were used. The P and EDR models of MCF7 and T47D cells were chronically exposed to increasing concentrations of Palbo to generate derivatives with acquired resistance to Palbo (PalboR). The transcriptomic profiles of P, endocrine-resistant (EndoR) and PalboR models were determined by RNA-seq. IC50s were determined by exposing MCF7, T47D, and ZR75-1 P and EndoR lines (n=12) to increasing concentrations of Palbo. Cell growth was assessed by methylene blue staining, and changes in the mRNA and protein levels of key cell cycle molecules were assessed by RT-PCR and Western blot, respectively. Gene expression data from the Cancer Dependency Map (DepMap), baseline tumors from the NeoPalAna (NCT01723774) and neoMONARCH (NCT02441946) neoadjuvant trials, as well as the TCGA and METABRIC datasets were interrogated for correlations of gene signatures and patient outcome (by KMPlot). Results: Palbo treatment resulted in a dose-dependent inhibition of the growth of P and EndoR BC cell lines, with varying degree of sensitivity among the models. GSEA analysis comparing the least sensitive (IC50\u003e350nM) vs. the most sensitive (IC50 Citation Format: Carmine De Angelis, Xiaoyong Fu, Maria Letizia Cataldo, Agostina Nardone, Valerie M. Jansen, Jamunarani Veeraraghavan, Sarmistha Nanda, Lanfang Qin, Vidyalakshmi Sethunath, Resel Pereira, Matteo Benelli, Ilenia Migliaccio, Luca Malorni, Joshua Donaldson, Pier Selenica, David N. Brown, Britta Weigelt, Jorge S. Reis-Filho, Ben H. Park, Sara A. Hurvitz, Dennis J. Slamon, Mothaffar F. Rimawi, Rinath Jeselsohn, Kent Osborne, Rachel Schiff. High levels of interferon-response gene signatures are associated with de novo and acquired resistance to CDK4/6 inhibitors in ER+ breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr GS2-01.