RNA-seq from atirmociclib resistant versus sensitive and vehicle treated HR+ HER2- ZR751  breast cancer xenografts .
We investigated the mechanisms of acquired resistance to the CDK4 selective inhibitor atirmociclib in HR+ HER2- breast cancer in vivo, using the ZR751 xenograft model. Atirmociclib resistant tumors appeared after long-term (>50 day) treatment with atirmociclib. Tumor material was isolated from resistant (85-day treatment) as well as sensitive/vehicle treated (3-day) tumor bearing mice and subjected to RNA-seq analysis. Overall design: To establish ZR751 tumors, (5-10) x106 ZR751 cells were subcutaneously implanted in the dorsal region of female NSG mice. When average tumor volume reached 150 mm3, tumor bearing mice were randomly assigned to treatment groups. Atirmociclib was then administered, PO, 60 mg/kg BID (7 hr apart). Following 3-day treatment (3 h after last dosing) of ZR751 xenograft bearing mice with vehicle and atirmociclib, tumors from 3–5 mice per treatment group were excised, segmented, and immediately flash frozen in liquid nitrogen. In a separate study, mice were treated for 84 to 91 days with atirmociclib, and tumors processed as above. Frozen tumor samples from all three treatment groups were then split for analysis by WB and mRNA sequencing (RNA-seq). For RNA processing and sequencing, tumor powder samples were provided directly to Genewiz (Azenta).