CDK4/6i treatment induces ferroptosis via downregulation of SLC7A11 mediated by SP1 for estrogen receptor positive breast cancers.

Abstract Purpose: Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6is) can significantly extend tumor response in patients with metastatic estrogen receptor–positive (ER+) breast cancer, but intrinsic and acquired resistance is common. Elucidation of the molecular features of CDK4/6i sensitivity and the efficiency of their combination with novel targeted cell death inducers may pave the way toward improving patient outcomes. Experimental Design: Ferroptosis-related characteristics were observed following treatment with the CDK4/6 inhibitor palbociclib. Transcriptomic analyses and functional assays were performed to determine the targets and regulatory mechanism of palbociclib in the ferroptosis pathway in ER+ breast cancer cell lines. A tumor xenograft model was used to study the synergistic antitumor effects of CDK4/6is in combination with ferroptosis inducers. Results: Ferroptosis, a form of regulated cell death driven by iron-dependent phospholipid peroxidation, is partly responsible for the efficacy of the CDK4/6 inhibitor palbociclib. Mechanistically, palbociclib downregulates cystine transporter SLC7A11 by inhibiting SP1 binding to the promoter region of SLC7A11. Furthermore, genetic or pharmacological inhibitors of SP1 or SLC7A11 can enhance cell sensitivity to palbociclib and synergistically inhibit ER+ breast cancer cell growth in combination with palbociclib. A syngeneic ER+ mouse mammary tumor model was used to verify that combined inhibition of SLC7A11 or SP1 and CDK4/6 resulted in marked suppression of tumor growth in vivo. Conclusions: Experimentally, ferroptosis represents some of the CDK4/6i-induced cell death response. This study illustrates the potential for targeting SLC7A11 in combination with CDK4/6 inhibitors and supports the investigation of combination therapy in ER+ breast cancer.