Targeting the androgen receptor (AR) signalling pathway remains the main therapeutic option for advanced prostate cancer. However, resistance to AR‐targeting inhibitors represents a great challenge, highlighting the need for new therapies. Activation of the PI3K/AKT pathway and increased expression of histone deacetylases (HDACs) are common aberrations in prostate cancer, suggesting that inhibition of such targets may be a viable therapeutic strategy for this patient population. Previous reports demonstrated that combination of PI3K inhibitors (PI3KIs) with histone deacetylase inhibitors (HDACIs) resulted in synergistic antitumour activities against preclinical models of prostate cancer. In this study, we demonstrate that the novel dual PI3K and HDAC inhibitor CUDC‐907 has promising antitumour activity against prostate cancer cell lines in vitro and castration‐resistant LuCaP 35CR patient‐derived xenograft (PDX) mouse model in vivo. CUDC‐907‐induced apoptosis was partially dependent on Mcl‐1, Bcl‐xL, Bim and c‐Myc. Further, down‐regulation of Wee1, CHK1, RRM1 and RRM2 contributed to CUDC‐907‐induced DNA damage and apoptosis. In the LuCaP 35CR PDX model, treatment with CUDC‐907 resulted in significant inhibition of tumour growth. These findings support the clinical development of CUDC‐907 for the treatment of prostate cancer.

中文翻译：

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CUDC-907，一种新型的PI3K和HDAC双重抑制剂，可治疗前列腺癌：抗肿瘤活性和分子作用机理。

靶向雄激素受体（AR）信号通路仍然是晚期前列腺癌的主要治疗选择。然而，对AR靶向抑制剂的耐药性代表了巨大的挑战，突出了对新疗法的需求。PI3K / AKT途径的激活和组蛋白脱乙酰基酶（HDACs）的表达增加是前列腺癌的常见畸变，这表明抑制此类靶标可能是该患者人群的可行治疗策略。先前的报道表明，PI3K抑制剂（PI3KIs）与组蛋白脱乙酰基酶抑制剂（HDACIs）的组合产生了针对前列腺癌临床前模型的协同抗肿瘤活性。在这个研究中，我们证明了新型的PI3K和HDAC双重抑制剂CUDC-907在体外和对去势抵抗性LuCaP 35CR患者来源的异种移植（PDX）小鼠模型中具有对前列腺癌细胞系的有希望的抗肿瘤活性。CUDC-907诱导的细胞凋亡部分取决于Mcl-1，Bcl-xL，Bim和c-Myc。此外，Wee1，CHK1，RRM1和RRM2的下调导致CUDC-907诱导的DNA损伤和细胞凋亡。在LuCaP 35CR PDX模型中，用CUDC-907处理可显着抑制肿瘤生长。这些发现支持CUDC-907用于前列腺癌治疗的临床开发。RRM1和RRM2导致CUDC-907诱导的DNA损伤和凋亡。在LuCaP 35CR PDX模型中，用CUDC-907处理可显着抑制肿瘤生长。这些发现支持CUDC-907用于前列腺癌治疗的临床开发。RRM1和RRM2导致CUDC-907诱导的DNA损伤和凋亡。在LuCaP 35CR PDX模型中，用CUDC-907处理可显着抑制肿瘤生长。这些发现支持CUDC-907用于前列腺癌治疗的临床开发。