转录辅助复合物FACT在Hedgehog通路失调肿瘤的发病和治疗中的作用和机制

Hedgehog（Hh）通路失调导致多类肿瘤发生，尽管该通路的靶向药物SMO抑制剂（SMOi）已获FDA批准，但其原发性和获得性耐药相继被发现。申请人所在实验室近年来发现靶向表观/转录调控因子BRD4或CDK7可抑制核心转录因子GLI表达来拮抗Hh通路失调肿瘤，为克服SMOi耐药打开了新思路。我们前期利用公共肿瘤数据库与功能基因组筛选对上千个表观/转录调控因子进行全面分析和初步验证，发现转录辅助复合物FACT参与Hh通路失调肿瘤发病并与Hh通路之间存在正反馈调节关系；已进入人体临床试验的FACT靶向药物可抑制Hh通路失调肿瘤并克服SMOi耐药。本项目拟在此基础上，深入解析FACT复合物与Hh通路正反馈调控的致癌功能与分子机理，并系统阐明FACT靶向药物抑制Hh通路失调肿瘤以及克服SMOi耐药的效果与机制，不仅能揭示该类肿瘤新的表观遗传致病机制，还能为其靶向治疗和克服临床耐药提供新策略。

Dysregulation of the Hedgehog (Hh) pathway causes tumorigenesis. Although the pathway-targeting drug SMO inhibitor (SMOi) has been approved by FDA, primary and acquired resistance have been identified. Our previous studies have demonstrated two epigenetic/transcriptional targeted therapeutic strategies, BET inhibition and CDK7 inhibition, could overcome both primary and acquired resistance to SMOi drugs by targeting the core transcription factor GLIs of Hh pathway. In our preliminary study, we performed public tumor database analysis and CRISPR-Cas9 screening to identify other potential epigenetic/transcriptional targeted strategies for suppressing aberrant Hh pathway and overcoming SMOi resistance. Our results demonstrated that Facilitates Chromatin Transcription (FACT) complex plays a critical role in Hedgehog-activated cancers. Moreover, we found a positive feedback regulation between FACT complex and Hh pathway. Importantly, the FACT complex targeted drug, which has entered human clinical trials, inhibits Hh pathway and overcomes SMOi resistance. On this basis, we will investigate the function and mechanism of positive feedback regulation between FACT complex and Hh pathway, as well as the role and mechanism of FACT complex targeted drug in suppressing Hedgehog-activated cancers and overcoming resistance to SMOi, which not only reveals new epigenetic pathogenesis of Hedgehog-activated cancers, but also provides new targets for targeted therapy and overcoming clinical drug resistance.