In this study, we show that RET is upregulated in breast cancer cell lines resistant to combined CDK4/6i and endocrine therapy compared to cells resistant to endocrine therapy alone, and inhibition of RET, either by siRNA-mediated knockdown or with the RET-selective inhibitor selpercatinib, alone or in combination with CDK4/6i and/or fulvestrant, reduced growth of CDK4/6i-resistant ER+ breast cancer cell lines and patient-derived organoids. Here, CDK4 is linked to breast cancer.