Targeting GSK3B in refractory B-cell malignancies

摘要 GSK3E是E-连环蛋白必不可少的负性调节因子，而E-连环蛋白的积累则是一种中枢调节因子。 癌症的致癌驱动因素。在实体瘤中，E-连环蛋白与Tcf7-因子形成转录复合体 MYC1-5的激活。与实体瘤形成鲜明对比的是，我们发现B细胞白血病和淋巴瘤并不是 仅豁免激活E-连环蛋白损伤，但对E-连环蛋白积聚高度敏感，严重依赖 论GSK3E介导的降解对其负调控：与其他癌症类型不同，E- B细胞恶性肿瘤中的连环蛋白抑制MYC的表达，并迅速诱导细胞死亡。而不是 转录激活因子Tcf7，我们在B细胞恶性肿瘤中的相互作用组研究表明，E-catenin形成了一种 抑制复合体与淋巴特异性伊卡洛斯锌指(IKZF)6-8因子。不是MYC激活，而是E- 连环蛋白组装的淋巴特异性Ikaros因子与抑制性核小体的多个成员 重构和去乙酰化(NuRD)9-10复合体，用于MYC的转录抑制。 GSK3E使E-连环蛋白外显子3的S/T-残基磷酸化，启动E-连环蛋白的降解。以杠杆作用 淋巴特异性抑制性E-连环蛋白复合体是以前未知的治疗易损性 检测了GSK3E小分子抑制剂。引人注目的是，目前正在临床使用的已建立的GSK3E抑制剂 对神经系统疾病和实体肿瘤的试验，在B细胞中的低纳摩尔浓度下有效 恶性肿瘤，导致E-连环蛋白大量积聚，抑制MYC和急性细胞死亡。临床前 基于患者来源的异种移植物的实验证实小分子GSK3E抑制剂具有靶向性 淋系特异性抑制性E-连环蛋白复合体参与克服难治性B细胞耐药 活体内的细胞恶性肿瘤。 基于这一发现，该提案的中心目标是将GSK3E抑制剂重新用于靶向 难治性B细胞恶性肿瘤中抑制性E-连环蛋白复合体的参与。鉴于四个GSK3E- 抑制剂已经经过了全面的临床开发，并在以下方面显示出良好的安全性 18项临床试验，我们预计这一强大的新方法可以迅速开发出来，使患者受益。 对于难治性B细胞恶性肿瘤，并在未来进一步扩展到T细胞恶性肿瘤。我们建议两个 目的是(1)阐明E-连环蛋白介导的肿瘤抑制的机制基础和(2)发展概念 利用E-连环蛋白-伊卡洛斯复合体的靶向激活对难治性B细胞进行治疗干预 恶性肿瘤。

Abstract GSK3E functions as essential negative regulator of E-catenin, while E-catenin accumulation represents a central oncogenic driver in cancer. In solid tumors, E-catenin forms complexes with TCF7-factors for transcriptional activation of MYC1-5. In striking contrast to solid tumors, we found that B-cell leukemias and lymphomas are not only exempt from activating E-catenin lesions but highly sensitive to E-catenin accumulation and critically depend on its negative regulation by GSK3E-mediated degradation: Unlike other cancer types, inducible activation of E- catenin in B-cell malignancies suppressed MYC-expression and rapidly induced cell death. Instead of the transcriptional activator TCF7, our interactome studies in B-cell malignancies revealed that E-catenin formed a repressive complex with lymphoid-specific Ikaros zinc finger (IKZF)6-8 factors. Instead of MYC-activation, E- catenin assembled lymphoid-specific Ikaros factors and multiple members of the repressive nucleosome remodeling and deacetylation (NuRD)9-10 complex for transcriptional repression of MYC. GSK3E phosphorylates S/T-residues in E-catenin exon 3, to initiate E-catenin- degradation. To leverage lymphoid-specific repressive E-catenin-complexes as previously unrecognized therapeutic vulnerability, we examined GSK3E small molecule inhibitors. Strikingly, established GSK3E-inhibitors that are currently in clinical trials for the neurological disorders and solid tumors, were effective at low nanomolar concentrations in B-cell malignancies, induced massive accumulation of E-catenin, repression of MYC and acute cell death. Preclinical experiments based on patient-derived xenografts validated small molecule GSK3E-inhibitors for targeted engagement of lymphoid-specific repressive E-catenin-complexes to overcome drug-resistance in refractory B- cell malignancies in vivo. Based on this discovery, the central goal of this proposal is to repurpose GSK3E-inhibitors for targeted engagement of repressive E-catenin-complexes in refractory B-cell malignancies. Given that four GSK3E- inhibitors have already undergone full clinical development and demonstrated favorable safety profiles in eighteen clinical trials, we anticipate that this powerful new approach can rapidly be developed to benefit patients with refractory B-cell malignancies and be further extended to T-cell malignancies in the future. We propose two Aims to (1) elucidate the mechanistic basis of E-catenin-mediated tumor suppression and to (2) develop concepts to leverage targeted activation of E-catenin-Ikaros complexes for therapeutic intervention in refractory B-cell malignancies.