PIK-75 通过阻断套细胞淋巴瘤中的 PI3K-AKT 信号传导和 MCL-1 表达来克服 venetoclax 耐药性。,American journal of cancer research

当前位置： X-MOL 学术 › Am J Cancer Res › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

PIK-75 通过阻断套细胞淋巴瘤中的 PI3K-AKT 信号传导和 MCL-1 表达来克服 venetoclax 耐药性。
American journal of cancer research Pub Date : 2022-03-15
Shengjian Huang ₁ , Yang Liu ₁ , Zhihong Chen ₁ , Michael Wang _{1,

2} , Vivian C Jiang ₁

Affiliation

治疗耐药性是套细胞淋巴瘤 (MCL) 患者临床面临的主要挑战，MCL 是 B 细胞淋巴瘤的一种侵袭性亚型。除了 FDA 批准的布鲁顿酪氨酸激酶 (BTK) 抑制剂外，多项临床试验已证明 venetoclax 靶向 BCL-2 的临床益处，并据报道可显着改善单独或与 BTK 抑制剂联合使用的难治性/复发性 MCL 患者的临床结果. 然而，对 venetoclax 的耐药性也不例外，并标志着新的临床挑战。为了破译驱动 venetoclax 耐药的潜在机制，我们建立了两个 MCL 细胞系 Mino-Re 和 Rec1-Re，它们对敏感的 Mino 和 Rec-1 的 venetoclax 具有获得性耐药性。使用反相蛋白质测定法 (RPPA)，一种不可知的蛋白质组学方法，我们确定了与 Mino-Re 和 Rec1-Re 细胞中获得性 venetoclax 抗性相关的可靶向信号通路。一组促生存信号被确定与 venetoclax 抗性密切相关，包括 MCL-1、BCL-xL 和 AKT 磷酸化的表达增加，以及 BIM、BAX 和 PTEN 的表达减少。基于对 venetoclax 敏感和耐药细胞系 Mino-Re 和 Rec1-Re 配对的 320 多种 FDA 批准/研究药物的高通量药物筛选，我们确定了能够克服这些药物中获得性 venetoclax 耐药性的最佳候选药物。细胞。最好的候选药物是 PIK-75，一种针对 PI3K 和 CDK9 的双重抑制剂。其克服 venetoclax 耐药性的作用在其他具有原发性 venetoclax 耐药性 (n=4) 和原发性患者样本 (n=21) 的细胞系中得到进一步证实。从机制上讲，PIK75 治疗有效地减少了具有获得性或原发性 venetoclax 抗性的细胞中升高的 MCL-1 表达和 AKT 活化，并导致有效的抗 MCL 活性以克服这些抗性。此外，PIK75 还可有效克服肿瘤微环境 (TME) 相关的 venetoclax 耐药性。此外，PIK-75 治疗可有效克服异种移植模型中的原发性和获得性 venetoclax 耐药性，并抑制肿瘤细胞向小鼠脾脏的扩散。总之，我们的数据表明 PIK-75 在克服初级、后天性、

"点击查看英文标题和摘要"

PIK-75 overcomes venetoclax resistance via blocking PI3K-AKT signaling and MCL-1 expression in mantle cell lymphoma.

Therapeutic resistance is the major challenge in clinic for patients with mantle cell lymphoma (MCL), an aggressive subtype of B-cell lymphoma. In addition to the FDA-approved Bruton's tyrosine kinase (BTK) inhibitors, multiple clinical trials have demonstrated clinical benefits in targeting BCL-2 by venetoclax and reported to greatly improve clinical outcome for refractory/relapsed patients with MCL alone or in combination with BTK inhibitors. However, resistance to venetoclax is no exception and marks as a new clinic challenge. To decode the underlying mechanisms driving venetoclax resistance, we established two MCL cell lines, Mino-Re and Rec1-Re, with acquired resistance to venetoclax from sensitive Mino and Rec-1. Using reverse phase protein assay (RPPA), an agnostic proteomic approach, we identified targetable signaling pathways that are associated with acquired venetoclax resistance in Mino-Re and Rec1-Re cells. A panel of pro-survival signals was identified to correlate well with venetoclax-resistance, including increased expression of MCL-1, BCL-xL and AKT phosphorylation, and decreased expression of BIM, BAX and PTEN. Based on a high throughput drug screening of over 320 FDA-approved/investigational drugs in the paired venetoclax-sensitive and -resistant cell lines Mino-Re and Rec1-Re, we identified the top candidates that are capable to overcome acquired venetoclax resistance in these cells. The best candidate is PIK-75, a dual inhibitor targeting both PI3K and CDK9. Its action to overcome venetoclax resistance was further confirmed in additional cell lines with primary venetoclax resistance (n=4) and primary patient samples (n=21). Mechanistically, PIK75 treatment potently diminished the elevated MCL-1 expression and AKT activation in cells with acquired or primary venetoclax resistance and resulted in potent anti-MCL activity to overcome these resistances. In addition, PIK75 is also potent in overcoming tumor microenvironment (TME)-associated venetoclax resistance. Furthermore, PIK-75 treatment is efficacious in overcoming primary and acquired venetoclax resistance in xenograft models and inhibited tumor cell dissemination to spleen in mice. Altogether, our data demonstrated that PIK-75 is highly potent in overcoming primary, acquired, or stromal cells-induced venetoclax resistances in MCL cells and revealed a new tumor vulnerability that can be exploited clinically in difficult to treat MCL cases, especially those with venetoclax resistance.

更新日期：2022-03-15

点击分享

点击收藏