Kinome Reprogramming Is a Targetable Vulnerability in ESR1 Fusion-Driven Breast Cancer.
Kinome Reprogramming Is a Targetable Vulnerability in ESR1 Fusion-Driven Breast Cancer.
复制标题
DOI：
10.1158/0008-5472.can-22-3484
复制
发表时间：
2023-10-02
期刊：
影响因子：
11.2
通讯作者：
Ellis, Matthew J.
中科院分区：
文献类型：
--
作者：
Gou, Xuxu;Kim, Beom-Jun;Anurag, Meenakshi;Lei, Jonathan T.;Young, Meggie N.;Holt, Matthew V.;Fandino, Diana;Vollert, Craig T.;Singh, Purba;Alzubi, Mohammad A.;Malovannaya, Anna;Dobrolecki, Lacey E.;Lewis, Michael T.;Li, Shunqiang;Foulds, Charles E.;Ellis, Matthew J.
使用药物珠状质谱分析ESR1易位和突变乳腺肿瘤的Kinome分析以及药物敏感性研究表明RET是一个治疗靶点。转录活性ESR1融合（ESR1- taf）是乳腺癌内分泌治疗（ET）抵抗的一个强有力的原因。ESR1-TAFs不能直接用于药物治疗，因为c端雌激素/抗雌激素结合结构域被易位的框架内伴侣基因序列所取代，这些基因序列赋予了构成性转激活。为了发现替代治疗方法，采用了一种基于质谱（MS）的激酶抑制剂下拉试验（KIPA）来鉴定由多种ESR1-TAFs上调的可药物激酶。随后的药物敏感性研究证实，尽管ESR1-TAF c端序列和结构多样性显著，RET激酶仍是一种常见的治疗易感性。含有ESR1-e6>YAP1 TAF的泛et耐药患者衍生异种移植模型的类器官和异种移植物被选择性RET抑制剂普拉塞替尼（pralsetinib）一致抑制，其程度与CDK4/6抑制剂palbociclib相似。总之，这些发现为临床评估RET抑制治疗esr1 - taf驱动的et耐药乳腺癌提供了临床前依据。使用药物珠状质谱分析ESR1易位和突变乳腺肿瘤的Kinome分析以及药物敏感性研究表明RET是一个治疗靶点。参见Wu和Subbiah的相关评论，第3159页
Kinome analysis of ESR1 translocated and mutated breast tumors using drug bead-based mass spectrometry followed by drug-sensitivity studies nominates RET as a therapeutic target. Transcriptionally active ESR1 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 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. Kinome analysis of ESR1 translocated and mutated breast tumors using drug bead-based mass spectrometry followed by drug-sensitivity studies nominates RET as a therapeutic target. See related commentary by Wu and Subbiah, p. 3159
影响因子：
3.8
作者：
Wang, Chunyu;Mayer, Julie Ann;Mazumdar, Abhijit;Brown, Powel H.
通讯作者：
Brown, Powel H.