Co-targeting RANK pathway treats and prevents acquired resistance to CDK4/6 inhibitors in luminal breast cancer

The combination of endocrine therapy (ET) and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors (CDK4/6i) was a hallmark in metastatic luminal breast cancer (BC). However, intrinsic and acquired resistance affects long-term efficacy. Here, we study the role of the receptor activator of nuclear factor-κB (RANK) pathway in CDK4/6i resistance. We find that RANK overexpression in luminal BC is associated with intrinsic resistance to CDK4/6i, both in vitro and in mouse xenografts, and decreased proliferation rate and chronic interferon (IFN) γ response are highlighted as resistance drivers. Gene expression data from the NeoPalAna CDK4/6i clinical trial, and studies with palbociclib-resistant cell lines, show that RANK is upregulated after treatment with CDK4/6i, supporting a role in acquired resistance. Our study shows that RANK ligand (RANKL) inhibitors can restore sensitivity to CDK4/6i and prevent acquired resistance. On the basis of these findings, we conclude that pharmacological inhibition of the RANK pathway through RANKL blocking could represent an add-on to ET + CDK4/6i, warranting further clinical studies. [Display omitted] •RANK signaling contributes to resistance to CDK4/6 inhibitors in ER+ breast cancer•RANK overexpression predicts resistance to CDK4/6 inhibitors in ER+ breast cancer•RANK pathway activates an interferon (IFN) response program•RANKL inhibitors treat and prevent/delay resistance to CDK4/6 inhibitors CDK4/6i and endocrine therapy are the first-line treatment for advanced luminal breast cancer. Gomes et al. show that the RANK pathway is involved in resistance to CDK4/6i, via interferon response and alternative cell cycle mediators. Moreover, RANKL inhibitors concomitant with CDK4/6i can increase therapy efficacy and delay acquired resistance.