The dysregulation of PI3K signaling has been implicated as an underlying mechanism associated with resistance to Bruton's tyrosine kinase inhibition by ibrutinib in both chronic lymphocytic leukemia and mantle cell lymphoma (MCL). Ibrutinib resistance has become a major unmet clinical need, and the development of therapeutics to overcome ibrutinib resistance will greatly improve the poor outcomes of ibrutinib-exposed MCL patients. CUDC-907 inhibits both PI3K and HDAC functionality to exert synergistic or additive effects. Therefore, the activity of CUDC-907 was examined in MCL cell lines and patient primary cells, including ibrutinib-resistant MCL cells. The efficacy of CUDC-907 was further examined in an ibrutinib-resistant MCL patient-derived xenograft (PDX) mouse model. The molecular mechanisms by which CUDC-907 dually inhibits PI3K and histone deacetylation were assessed using reverse protein array, immunoblotting, and chromatin immunoprecipitation (ChIP) coupled with sequencing. We showed evidence that CUDC-907 treatment increased histone acetylation in MCL cells. We found that CUDC-907 caused decreased proliferation and increased apoptosis in MCL in vitro and in vivo MCL models. In addition, CUDC-907 was effective in inducing lethality in ibrutinib-resistant MCL cells. Lastly, CUDC-907 treatment increased histone acetylation in MCL cells. Overall, these studies suggest that CUDC-907 may be a promising therapeutic option for relapsed or resistant MCL.

中文翻译：

---

PI3K信号转导和组蛋白去乙酰化的双重抑制作用可停止增殖，并在套细胞淋巴瘤中诱导致死性。

在慢性淋巴细胞性白血病和套细胞淋巴瘤（MCL）中，PI3K信号的失调被认为是与依鲁替尼对Bruton酪氨酸激酶抑制产生抗性相关的潜在机制。依鲁替尼耐药已成为临床上尚未满足的主要需求，克服艾鲁替尼耐药的治疗药物的开发将大大改善接受依鲁替尼治疗的MCL患者的不良预后。CUDC-907同时抑制PI3K和HDAC功能，以发挥协同作用或累加作用。因此，在MCL细胞系和患者原代细胞（包括对依鲁替尼耐药的MCL细胞）中检查了CUDC-907的活性。在耐依鲁替尼的MCL患者异种移植（PDX）小鼠模型中进一步检查了CUDC-907的功效。使用反向蛋白阵列，免疫印迹和染色质免疫沉淀（ChIP）结合测序，评估了CUDC-907双重抑制PI3K和组蛋白脱乙酰化的分子机制。我们显示的证据表明，CUDC-907处理可增加MCL细胞中的组蛋白乙酰化。我们发现CUDC-907导致体外和体内MCL模型中MCL的增殖减少和凋亡增加。此外，CUDC-907可有效诱导对依鲁替尼耐药的MCL细胞的致死性。最后，CUDC-907处理增加了MCL细胞中的组蛋白乙酰化。总体而言，这些研究表明，CUDC-907可能是复发或耐药MCL的有前途的治疗选择。我们显示的证据表明，CUDC-907处理可增加MCL细胞中的组蛋白乙酰化。我们发现CUDC-907导致体外和体内MCL模型中MCL的增殖减少和凋亡增加。此外，CUDC-907可有效诱导对依鲁替尼耐药的MCL细胞的致死性。最后，CUDC-907处理增加了MCL细胞中的组蛋白乙酰化。总体而言，这些研究表明，CUDC-907可能是复发或耐药MCL的有前途的治疗选择。我们显示的证据表明，CUDC-907处理可增加MCL细胞中的组蛋白乙酰化。我们发现CUDC-907导致体外和体内MCL模型中MCL的增殖减少和凋亡增加。此外，CUDC-907可有效诱导对依鲁替尼耐药的MCL细胞的致死性。最后，CUDC-907处理增加了MCL细胞中的组蛋白乙酰化。总体而言，这些研究表明，CUDC-907可能是复发或耐药MCL的有前途的治疗选择。