RANK expression and Luminal BC response to CDK4/6 inhibitors

The combination of endocrine therapy (ET) with CDK4/6 inhibitors (CDK4/6i) was the most recent life-changing hallmark in metastatic Luminal breast cancer (BC). However, intrinsic and acquired resistance affect long-term efficacy. Here, we studied the role of receptor activator of nuclear factor-kB (RANK) pathway in CDK4/6i resistance. We found that RANK overexpression in Luminal BC associates with intrinsic resistance to CDK4/6i, both in vitro and in mouse xenografts. Transcriptomic analysis of mouse tumors highlighted decreased proliferation rate and chronic interferon (IFN)-response as resistance drivers. The transcriptomic profiles of tumor tissue from MCF-7 and MCF-7 RANK OE xenografts implanted in NSG mice, collected after 21 days of treatment with Vehicle, Palbociclib+Fulvestrant or Palbociclib+Fulvestrant+OPG-Fc, were analyzed by RNASeq. 2-3 tumors per group were included.