Therapeutic Targeting of Nemo-like Kinase in Primary and Acquired Endocrine-resistant Breast Cancer.
Therapeutic Targeting of Nemo-like Kinase in Primary and Acquired Endocrine-resistant Breast Cancer.
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DOI：
10.1158/1078-0432.ccr-20-2961
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发表时间：
2021-05-01
期刊：
影响因子：
--
通讯作者：
Wang XS
中科院分区：
文献类型：
--
作者：
Wang X;Veeraraghavan J;Liu CC;Cao X;Qin L;Kim JA;Tan Y;Loo SK;Hu Y;Lin L;Lee S;Shea MJ;Mitchell T;Li S;Ellis MJ;Hilsenbeck SG;Schiff R;Wang XS
内分泌抵抗仍然是雌激素受体(ER)阳性乳腺癌的主要临床挑战。尽管针对已知生存信号的药物的临床试验结果令人鼓舞，但复发仍然是不可避免的。在未知的逃生途径中发现新的药物靶点的需求尚未得到满足。在这里，我们报告了Nemo-like Kinase(NLK)作为一个新的可操作的激酶靶点，在内分泌耐药的乳腺癌中赋予以前未知的生存信号。用MTS法检测抑制NLK对内分泌耐药乳腺癌细胞株活力的影响。用激酶法检测VX-702对NLK活性的影响。采用免疫沉淀法、激酶法、荧光素酶测定法和RNAseq法检测NLK对ER及其辅活化子SRC-3的调节作用。在细胞系和患者来源的异种移植瘤模型上测试VX-702和Everolimus的治疗效果。NLK的过度表达降低了内分泌反应性，并与他莫昔芬治疗患者的不良预后有关。从机制上讲，NLK最终可能通过增强ERα及其关键辅助激活因子SRC3的磷酸化来调节ERα的转录活性而发挥作用。通过对一个激酶图谱数据库的查询，我们发现并验证了一个高度选择性的双重p38/NLK抑制剂VX-702。VX-702与mTOR抑制剂Everolimus联合给药，对获得性或非获得性内分泌耐药的细胞系和患者来源的异种移植瘤模型显示了显著的治疗效果。总之，这项研究揭示了NLK信号活跃的内分泌抵抗型乳腺癌的治疗调节的潜力。
Endocrine resistance remains a major clinical challenge in estrogen-receptor (ER) positive breast cancer. Despite the encouraging results from clinical trials for the drugs targeting known survival signaling, relapse is still inevitable. There is an unmet need to discover new drug targets in the unknown escape pathways. Here we report Nemo-Like Kinase (NLK) as a new actionable kinase target that endows previously uncharacterized survival signaling in endocrine resistant breast cancer. The effects of NLK inhibition on the viability of endocrine resistant breast cancer cell lines were examined by MTS assay. The effect of VX-702 on NLK activity was verified by kinase assay. The modulation of ER and its coactivator SRC-3 by NLK were examined by immunoprecipitation, kinase assay, luciferase assay, and RNAseq. The therapeutic effects of VX-702 and Everolimus were tested on cell line- and patient-derived xenograft tumor models. NLK overexpression endow reduced endocrine responsiveness and is associated with worse outcome of tamoxifen-treated patients. Mechanistically, NLK may function at last in part via enhancing the phosphorylation of ERα and its key coactivator SRC-3 to modulate ERα transcriptional activity. Through interrogation of a kinase-profiling database, we uncovered and verified a highly selective dual p38/NLK inhibitor, VX-702. Co-administration of VX-702 with the mTOR inhibitor Everolimus demonstrated a significant therapeutic effect in cell line- and patient-derived xenograft tumor models of acquired or de novo endocrine resistance. Together, this study reveals the potential of therapeutic modulation of NLK for the management of the endocrine-resistant breast cancers with active NLK signaling.
DOI：
10.1186/bcr2179
发表时间：
2008
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Miller WR
通讯作者：
Miller WR