转录活跃的ESR1基因融合体（ESR1-TAF）是乳腺癌内分泌治疗（ET）抵抗的一个强有力的原因。由于C端雌激素/抗雌激素结合域被转位的同框合作伴侣基因序列所替代，ESR1-TAF不直接可药物化，这些序列使其具有组成性转录活化特征。为了发现其他治疗方法，利用基于质谱的激酶抑制剂扯出试验（KIPA）识别ESR1-TAF上调的可药物化激酶。随后，通过药物敏感性的探索，验证了RET激酶作为一个普遍的治疗易感性，尽管ESR1-TAF C端序列和结构多样性很大。来自患有ESR1-e6>YAP1 TAF的全ET抵抗患者源异种移植模型（PDX）的器官样本和异种移植均通过选择性RET抑制剂Pralsetinib等效抑制，与CDK4/6抑制剂Palbociclib相当。这些发现提供了临床理由，推动对RET抑制剂在治疗ESR1-TAF驱动的ET抵抗性乳腺癌中的临床评估。

Transcriptionally active ESR1 gene fusions (ESR1-TAF) are a potent cause of breast cancer endocrine therapy (ET) resistance. ESR1-TAFs are not directly druggable because the C-terminal estrogen/anti-estrogen binding domain is replaced with translocated in-frame partner gene sequences that confer constitutive transactivation. To discover alternative treatments, a mass spectrometry (MS)-based kinase inhibitor pulldown assay (KIPA) was deployed to identify druggable kinases that are upregulated by diverse ESR1-TAFs. Subsequent explorations of drug sensitivity validated RET kinase as a common therapeutic vulnerability despite remarkable ESR1-TAF C-terminal sequence and structural diversity. Organoids and xenografts from a pan-ET resistant patient-derived xenograft (PDX) model that harbors the ESR1-e6>YAP1 TAF were concordantly inhibited by the selective RET inhibitor pralsetinib to a similar extent as the CDK4/6 inhibitor palbociclib. Together, these findings provide preclinical rationale for clinical evaluation of RET inhibition for the treatment of ESR1-TAF-driven ET resistant breast cancer.