Department of Clinical Trials Center, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
Institute of Translational Medicine, Shanghai University, Shanghai, 200444, China.
Med Oncol. 2022 Sep 7;39(12):188. doi: 10.1007/s12032-022-01794-w.
Abnormally activated Hedgehog (Hh) pathway has been linked to multiple types of cancers including medulloblastoma (MB). Current Hh-targeted drug development projects mainly focus on antagonizing the upstream oncoprotein Smoothened (Smo). However, the effectiveness of Smo inhibitors is compromised by primary and acquired resistance, which is caused by mutations of Smo or other downstream components. Here, we conducted a cellular screening of small-molecule compounds and identified ABT-737 as a selective Hh inhibitor resulting in active suppression of human Hh-dependent MB cells. Mechanistically, ABT-737 suppressed Hh signals far-downstream of Smo and Sufu at Gli transcriptional effector level. In line with this, ABT-737 potentially inhibited wild-type and drug-resistant mutant Smo. More importantly, ABT-737 also delayed the growth of drug-refractory Hh-dependent MB xenografts derived from genetically engineered mouse model in vivo. These findings identify ABT-737 as a therapeutical substance for cancers with excessive Hh signaling activity, especially for those with primary or acquired resistance to Smo inhibitors in clinic.
异常激活的 Hedgehog（Hh）信号通路与多种癌症有关，包括髓母细胞瘤（MB）。目前的 Hh 靶向药物研发项目主要集中在拮抗上游致癌蛋白 Smoothened（Smo）。然而，Smo 抑制剂的有效性受到原发性和获得性耐药的影响，这是由 Smo 或其他下游成分的突变引起的。在这里，我们进行了小分子化合物的细胞筛选，发现 ABT-737 是一种选择性的 Hh 抑制剂，可有效抑制人 Hh 依赖性 MB 细胞。在机制上，ABT-737 在 Gli 转录效应因子水平上抑制 Smo 和 Sufu 下游的 Hh 信号。与此一致的是，ABT-737 可能抑制野生型和耐药性突变型 Smo。更重要的是，ABT-737 还延迟了体内来源于基因工程小鼠模型的耐药性 Hh 依赖性 MB 异种移植物的生长。这些发现确定了 ABT-737 是一种治疗过度 Hh 信号活性相关癌症的药物，特别是对那些对 Smo 抑制剂有原发性或获得性耐药的癌症。
