谱系可塑性是一种治疗引起的药物耐受性。在前列腺癌中，雄激素受体（AR）通路抑制剂可能导致肿瘤复发和AR信号丧失的堆积，并从管腔状态转变为其他程序。然而，在AR靶向治疗压力下，调控谱系可塑性发展的分子和信号机制尚不完全清楚。在这里，受体酪氨酸激酶（RTKs）的调查确认ROR2是AR通路抑制后最显著的上调RTK，通过促进干细胞样和神经网络而参与谱系可塑性。机制上，ROR2通过激活ERK/CREB信号通路来调控谱系承诺转录因子ASCL1的表达。总之，我们的发现将ROR2提名为一个潜在的治疗靶点，以逆转ENZ诱导的可塑表型，并可能使肿瘤对AR通路抑制剂重新敏感。 版权所有©2023作者。由爱思唯尔公司出版。版权所有。

Lineage plasticity is a form of therapy-induced drug resistance. In prostate cancer, androgen receptor (AR) pathway inhibitors potentially lead to the accretion of tumor relapse with loss of AR signaling and a shift from a luminal state to an alternate program. However, the molecular and signaling mechanisms orchestrating the development of lineage plasticity under the pressure of AR-targeted therapies are not fully understood. Here, a survey of receptor tyrosine kinases (RTKs) identifies ROR2 as the top upregulated RTK following AR pathway inhibition, which feeds into lineage plasticity by promoting stem-cell-like and neuronal networks. Mechanistically, ROR2 activates the ERK/CREB signaling pathway to modulate the expression of the lineage commitment transcription factor ASCL1. Collectively, our findings nominate ROR2 as a potential therapeutic target to reverse the ENZ-induced plastic phenotype and potentially re-sensitize tumors to AR pathway inhibitors.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.