Thy Sophia, Hommel Alexandra, Meneceur Sarah, Bartkowiak Anna L, Schulz Wolfgang A, Niegisch Günter, Hoffmann Michèle J
Department of Urology, Medical Faculty, Heinrich-Heine-University Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany.
Cancers (Basel). 2021 Mar 18;13(6):1376. doi: 10.3390/cancers13061376.
Muscle-invasive urothelial carcinoma (UC) is treated with cisplatin-based chemotherapy, which is only moderately efficient, mostly due to development of resistance. New therapy approaches are therefore urgently needed. Epigenetic alterations due to frequent mutations in epigenetic regulators contribute to development of the disease and to treatment resistance, and provide targets for novel drug combination therapies. Here, we determined the cytotoxic impact of the second-generation bromodomain protein inhibitor (BETi) PLX51107 on UC cell lines (UCC) and normal HBLAK control cells. PLX51107 inhibited proliferation, induced apoptosis, and acted synergistically with the histone deacetylase inhibitor romidepsin. While PLX51107 caused significant DNA damage, DNA damage signaling and DNA repair were impeded, a state defined as BRCAness. Accordingly, the drug strongly synergized with cisplatin more efficiently than romidepsin, and with the PARP inhibitor talazoparib to inhibit proliferation and induce cell death in UCC. Thus, a BETi can be used to "episensitize" UC cells to cytotoxic chemotherapy and inhibitors of DNA repair by inducing BRCAness in non BRCA1/2 mutated cancers. In clinical applications, the synergy between PLX51107 and other drugs should permit significant dosage reductions to minimize effects on normal tissues.
肌层浸润性尿路上皮癌（UC）采用以顺铂为基础的化疗进行治疗，但其疗效仅为中等，主要原因是产生了耐药性。因此，迫切需要新的治疗方法。表观遗传调节因子频繁突变导致的表观遗传改变促成了该疾病的发展和治疗耐药性，并为新型联合药物疗法提供了靶点。在此，我们确定了第二代溴结构域蛋白抑制剂（BETi）PLX51107对UC细胞系（UCC）和正常HBLAK对照细胞的细胞毒性影响。PLX51107抑制增殖、诱导凋亡，并与组蛋白去乙酰化酶抑制剂罗米地辛协同作用。虽然PLX51107造成了显著的DNA损伤，但DNA损伤信号传导和DNA修复受到阻碍，这种状态被定义为BRCAness。相应地，该药物与顺铂协同作用比罗米地辛更有效，并且与PARP抑制剂他拉唑帕尼协同作用，以抑制UCC中的增殖并诱导细胞死亡。因此，一种BETi可用于通过在非BRCA1/2突变癌症中诱导BRCAness，使UC细胞对细胞毒性化疗和DNA修复抑制剂“表观致敏”。在临床应用中，PLX51107与其他药物之间的协同作用应能显著降低剂量，以尽量减少对正常组织的影响。
