Inhibition of the FACT Complex Targets Aberrant Hedgehog Signaling and Overcomes Resistance to Smoothened Antagonists
Inhibition of the FACT Complex Targets Aberrant Hedgehog Signaling and Overcomes Resistance to Smoothened Antagonists
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FACT 复合物的抑制作用针对异常的刺猬信号传导并克服对平滑拮抗剂的耐药性
DOI：
10.1158/0008-5472.can-20-3186
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发表时间：
2021-06-01
期刊：
影响因子：
11.2
通讯作者：
Tang, Yujie
中科院分区：
文献类型：
--
作者：
Mo, Jialin;Liu, Fang;Tang, Yujie
这项研究将FACT抑制确定为克服Smoothened抑制剂耐药性的抗hedgehog治疗策略，并为启动FACT靶向药物CBL 0137对抗hedgehog驱动的癌症的临床试验提供临床前支持。Hedgehog信号传导在血液恶性肿瘤和实体瘤中被异常激活，靶向它是针对这些癌症的有希望的治疗策略。对临床上可用的刺猬靶向Smoothened抑制剂（SMOi）药物的耐药性已成为刺猬驱动的癌症治疗中的关键问题。我们先前的研究确定BET和CDK 7的抑制是克服SMOi抗性的两种表观遗传/转录靶向治疗策略，为抗刺猬药物开发提供了有希望的方向。为了揭示抑制异常hedgehog活性的其他策略，在这里，我们使用靶向hedgehog驱动的髓母细胞瘤细胞中的表观遗传和转录调节因子的单向导RNA文库进行了CRISPR-Cas9筛选，并结合肿瘤数据集分析。结构特异性识别蛋白1（SSRP 1）是促进染色质转录（FACT）复合物的一个亚基，被认为是刺猬诱导的重要癌基因和治疗靶点。已经进入癌症临床试验的FACT抑制剂CBL 0137有效地抑制了多种SMOi响应性和SMOi抗性hedgehog驱动的癌症模型的体外和体内生长。从机制上讲，CBL 0137通过靶向Hedgehog途径核心转录因子GLI 1和GLI 2的转录来发挥抗Hedgehog活性。SSRP 1结合GLI 1和GLI 2的启动子区域，而CBL 0137处理基本上破坏了这些相互作用。此外，CBL 0137与BET或CDK 7抑制剂协同作用，以拮抗异常的刺猬途径和刺猬驱动的癌症模型的生长。总之，这些结果将FACT抑制鉴定为用于治疗刺猬驱动的癌症和克服SMOi抗性的有前景的表观遗传/转录靶向治疗策略。重要性：这项研究将FACT抑制确定为克服Smoothened抑制剂耐药性的抗hedgehog治疗策略，并为启动FACT靶向药物CBL 0137对抗hedgehog驱动的癌症的临床试验提供临床前支持。
This study identifies FACT inhibition as an anti-hedgehog therapeutic strategy for overcoming resistance to Smoothened inhibitors and provides preclinical support for initiating clinical trials of FACT-targeted drug CBL0137 against hedgehog-driven cancers. Hedgehog signaling is aberrantly activated in hematologic malignancies and solid tumors, and targeting it is a promising therapeutic strategy against these cancers. Resistance to clinically available hedgehog-targeted Smoothened inhibitor (SMOi) drugs has become a critical issue in hedgehog-driven cancer treatment. Our previous studies identified inhibition of BET and CDK7 as two epigenetic/transcriptional-targeted therapeutic strategies for overcoming SMOi resistance, providing a promising direction for anti-hedgehog drug development. To uncover additional strategies for inhibiting aberrant hedgehog activity, here we performed CRISPR-Cas9 screening with an single-guide RNA library targeting epigenetic and transcriptional modulators in hedgehog-driven medulloblastoma cells, combined with tumor dataset analyses. Structure specific recognition protein 1 (SSRP1), a subunit of facilitates chromatin transcription (FACT) complex, was identified as a hedgehog-induced essential oncogene and therapeutic target in hedgehog-driven cancer. The FACT inhibitor CBL0137, which has entered clinical trials for cancer, effectively suppressed in vitro and in vivo growth of multiple SMOi-responsive and SMOi-resistant hedgehog-driven cancer models. Mechanistically, CBL0137 exerted anti-hedgehog activity by targeting transcription of GLI1 and GLI2, which are core transcription factors of the hedgehog pathway. SSRP1 bound the promoter regions of GLI1 and GLI2, while CBL0137 treatment substantially disrupted these interactions. Moreover, CBL0137 synergized with BET or CDK7 inhibitors to antagonize aberrant hedgehog pathway and growth of hedgehog-driven cancer models. Taken together, these results identify FACT inhibition as a promising epigenetic/transcriptional-targeted therapeutic strategy for treating hedgehog-driven cancers and overcoming SMOi resistance. Significance: This study identifies FACT inhibition as an anti-hedgehog therapeutic strategy for overcoming resistance to Smoothened inhibitors and provides preclinical support for initiating clinical trials of FACT-targeted drug CBL0137 against hedgehog-driven cancers.