CDC7 抑制通过 MYC 降解损害肺和前列腺肿瘤中的神经内分泌转化。
CDC7 inhibition impairs neuroendocrine transformation in lung and prostate tumors through MYC degradation.
发表日期：2024 Jul 26
作者：
Alvaro Quintanal-Villalonga, Kenta Kawasaki, Esther Redin, Fathema Uddin, Swanand Rakhade, Vidushi Durani, Amin Sabet, Moniquetta Shafer, Wouter R Karthaus, Samir Zaidi, Yingqian A Zhan, Parvathy Manoj, Harsha Sridhar, Dennis Kinyua, Hong Zhong, Barbara P Mello, Metamia Ciampricotti, Umesh K Bhanot, Irina Linkov, Juan Qiu, Radhika A Patel, Colm Morrissey, Sanjoy Mehta, Jesse Barnes, Michael C Haffner, Nicholas D Socci, Richard P Koche, Elisa de Stanchina, Sonia Molina-Pinelo, Sohrab Salehi, Helena A Yu, Joseph M Chan, Charles M Rudin
来源：
Signal Transduction and Targeted Therapy
摘要：
神经内分泌（NE）转化是肺腺癌和前列腺癌靶向治疗的一种耐药机制，导致预后不良。迄今为止，即使可以通过肿瘤蛋白 P53 (TP53) 和视网膜母细胞瘤转录辅阻遏物 1 (RB1) 突变的发生来识别具有高转化风险的患者，也没有可用于预防或延迟组织学转化的治疗策略。在 TP53/RB1 共失活后，NE 转化的初始步骤中，肿瘤中细胞周期激酶细胞分裂周期 7 (CDC7) 发生上调，导致诱导对 CDC7 抑制剂 simurosertib 的敏感性。 CDC7 抑制通过诱导蛋白酶体介导的 MYC 原癌基因 (MYC) 降解，抑制 NE 转分化，并延长体内 NE 转化模型对靶向治疗的反应，这与干细胞性和组织学转化有关。抗降解 MYC 亚型的异位过度表达重建了靶向治疗中观察到的 NE 转化表型，即使在 simurosertib 存在的情况下也是如此。 CDC7 抑制还显着延长了肺癌和前列腺小细胞癌模型中对标准细胞毒素（顺铂、伊立替康）的反应。这些结果表明 CDC7 抑制作为一种限制谱系可塑性的治疗策略，以及有效治疗从头或转化后的 NE 肿瘤。由于 simurosertib 临床疗效试验正在进行中，这一概念可以很容易地转化为有转化风险的患者。© 2024。作者。
Neuroendocrine (NE) transformation is a mechanism of resistance to targeted therapy in lung and prostate adenocarcinomas leading to poor prognosis. Up to date, even if patients at high risk of transformation can be identified by the occurrence of Tumor Protein P53 (TP53) and Retinoblastoma Transcriptional Corepressor 1 (RB1) mutations in their tumors, no therapeutic strategies are available to prevent or delay histological transformation. Upregulation of the cell cycle kinase Cell Division Cycle 7 (CDC7) occurred in tumors during the initial steps of NE transformation, already after TP53/RB1 co-inactivation, leading to induced sensitivity to the CDC7 inhibitor simurosertib. CDC7 inhibition suppressed NE transdifferentiation and extended response to targeted therapy in in vivo models of NE transformation by inducing the proteasome-mediated degradation of the MYC Proto-Oncogen (MYC), implicated in stemness and histological transformation. Ectopic overexpression of a degradation-resistant MYC isoform reestablished the NE transformation phenotype observed on targeted therapy, even in the presence of simurosertib. CDC7 inhibition also markedly extended response to standard cytotoxics (cisplatin, irinotecan) in lung and prostate small cell carcinoma models. These results nominate CDC7 inhibition as a therapeutic strategy to constrain lineage plasticity, as well as to effectively treat NE tumors de novo or after transformation. As simurosertib clinical efficacy trials are ongoing, this concept could be readily translated for patients at risk of transformation.© 2024. The Author(s).