美国密歇根大学Arul M. Chinnaiyan研究小组在前列腺癌中实现对SWI/SNF ATP酶的靶向降解。相关论文于2021年12月22日在线发表在《自然》杂志上。

研究人员开发了一种SWI/SNF ATP酶亚基SMARCA2和SMARCA4的蛋白分解靶向嵌合体（PROTAC）降解剂，称为AU-15330。相对于正常和其他癌细胞系，雄性激素受体（AR）⁺ forkhead box A1（FOXA1）⁺前列腺癌细胞对SMARCA2和SMARCA4的双重降解非常敏感。SWI/SNF ATP酶降解能迅速压实由转录因子结合的顺式调控元件，这些转录因子能驱动前列腺癌细胞增殖，即AR、FOXA1、ERG和MYC，从而使它们脱离染色质，使其核心增强子回路失效，并废除下游的致癌基因程序。

SWI/SNF ATP酶的降解还破坏了超级增强子和启动子环路的相互作用，而这些作用能够重塑AR、FOXA1和MYC致癌基因本身的高表达。AU-15330能有效地抑制前列腺癌异种移植模型中的肿瘤生长，并与AR拮抗剂恩扎鲁胺协同作用，甚至能在无毒性的情况下诱发去势抵抗型前列腺癌（CRPC）模型的疾病缓解。因此，阻碍SWI/SNF介导的增强子可及性是一种有希望的治疗方法，可用于增强子噬性癌症。

据悉，SWI/SNF复合物在染色质重塑中具有关键作用，并且在20%以上的癌症中发生改变。

附：英文原文

Title: Targeting SWI/SNF ATPases in enhancer-addicted prostate cancer

Author: Xiao, Lanbo, Parolia, Abhijit, Qiao, Yuanyuan, Bawa, Pushpinder, Eyunni, Sanjana, Mannan, Rahul, Carson, Sandra E., Chang, Yu, Wang, Xiaoju, Zhang, Yuping, Vo, Josh N., Kregel, Steven, Simko, Stephanie A., Delekta, Andrew D., Jaber, Mustapha, Zheng, Heng, Apel, Ingrid J., McMurry, Lisa, Su, Fengyun, Wang, Rui, Zelenka-Wang, Sylvia, Sasmal, Sanjita, Khare, Leena, Mukherjee, Subhendu, Abbineni, Chandrasekhar, Aithal, Kiran, Bhakta, Mital S., Ghurye, Jay, Cao, Xuhong, Navone, Nora M., Nesvizhskii, Alexey I., Mehra, Rohit, Vaishampayan, Ulka, Blanchette, Marco, Wang, Yuzhuo, Samajdar, Susanta, Ramachandra, Murali, Chinnaiyan, Arul M.

Issue&Volume: 2021-12-22

Abstract: The switch/sucrose non-fermentable (SWI/SNF) complex has a crucial role in chromatin remodelling1 and is altered in over 20% of cancers2,3. Here we developed a proteolysis-targeting chimera (PROTAC) degrader of the SWI/SNF ATPase subunits, SMARCA2 and SMARCA4, called AU-15330. Androgen receptor (AR)+ forkhead box A1 (FOXA1)+ prostate cancer cells are exquisitely sensitive to dual SMARCA2 and SMARCA4 degradation relative to normal and other cancer cell lines. SWI/SNF ATPase degradation rapidly compacts cis-regulatory elements bound by transcription factors that drive prostate cancer cell proliferation, namely AR, FOXA1, ERG and MYC, which dislodges them from chromatin, disables their core enhancer circuitry, and abolishes the downstream oncogenic gene programs. SWI/SNF ATPase degradation also disrupts super-enhancer and promoter looping interactions that wire supra-physiologic expression of the AR, FOXA1 and MYC oncogenes themselves. AU-15330 induces potent inhibition of tumour growth in xenograft models of prostate cancer and synergizes with the AR antagonist enzalutamide, even inducing disease remission in castration-resistant prostate cancer (CRPC) models without toxicity. Thus, impeding SWI/SNF-mediated enhancer accessibility represents a promising therapeutic approach for enhancer-addicted cancers.

DOI: 10.1038/s41586-021-04246-z

Source: https://www.nature.com/articles/s41586-021-04246-z