PIK-75 overcomes venetoclax resistance via blocking PI3K-AKT signaling and MCL-1 expression in mantle cell lymphoma.
PIK-75 overcomes venetoclax resistance via blocking PI3K-AKT signaling and MCL-1 expression in mantle cell lymphoma.
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发表时间：
2022
影响因子：
5.3
通讯作者：
Shengjian Huang;Yang Liu;Zhihong Chen;Michael Wang;V. Jiang
中科院分区：
文献类型：
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作者：
Shengjian Huang;Yang Liu;Zhihong Chen;Michael Wang;V. Jiang
套细胞淋巴瘤（MCL）是B细胞淋巴瘤的一种侵袭性亚型，其耐药性是临床上面临的主要挑战。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维奈托克靶向BCL-2的临床获益，并报告可极大改善MCL单药或与BTK抑制剂联合治疗的难治性/复发性患者的临床结局。然而，对维奈托克的耐药性也不例外，并标志着一个新的临床挑战。为了解码驱动维奈托克抗性的潜在机制，我们建立了两种MCL细胞系Mino-Re和Rec 1-Re，其从敏感的Mino和Rec-1获得对维奈托克的抗性。使用反相蛋白质测定（RPPA），一种不可知的蛋白质组学方法，我们确定了与获得性维奈托克耐药Mino-Re和Rec 1-Re细胞相关的靶向信号通路。一组促存活信号被鉴定为与维奈托克抗性良好相关，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。基于在配对的维奈托克敏感和耐药细胞系Mino-Re和Rec 1-Re中对超过320种FDA批准/研究药物进行的高通量药物筛选，我们确定了能够克服这些细胞中获得性维奈托克耐药性的最佳候选药物。最好的候选者是PIK-75，一种靶向PI 3 K和CDK 9的双重抑制剂。其克服维奈托克耐药性的作用在具有原发性维奈托克耐药性的其他细胞系（n=4）和原发性患者样本（n=21）中得到进一步证实。从机制上讲，PIK 75处理有效地降低了具有获得性或原发性维奈托克抗性的细胞中升高的MCL-1表达和AKT活化，并产生有效的抗MCL活性以克服这些抗性。此外，PIK 75还能有效克服肿瘤微环境（TME）相关的维奈托克耐药性。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维奈托克耐药性，并抑制小鼠中肿瘤细胞向脾脏的传播。总之，我们的数据表明，PIK-75在克服MCL细胞中的原发性、获得性或基质细胞诱导的维奈托克耐药性方面非常有效，并揭示了一种新的肿瘤脆弱性，可在临床上用于难以治疗的MCL病例，特别是具有维奈托克耐药性的病例。
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.