Teicher Beverly A, Dexheimer Thomas S, Chen Li, Silvers Thomas, Jones Eric M, Coussens Nathan P, Eder J Paul, Doroshow James H
Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD 20892, United States of America.
Applied and Developmental Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, United States of America.
Exp Mol Pathol. 2025 Jun 27;143:104978. doi: 10.1016/j.yexmp.2025.104978.
The potential of novobiocin, recently identified to be a DNA POLѲ inhibitor, to augment cancer chemotherapy was explored in the late 1980s and early 1990s in tumor cells, tumor-bearing mice and in Phase 1 clinical trial in combination with cyclophosphamide or cisplatin. Genetic alterations which may increase or decrease POLѲ inhibitor effects have been elucidated. Thirty patient-derived tumor cell lines with known BRCA, ATM, ATR, POLѲ, XRCC1, PALB2, PARP1, LIG3 alterations as well as know gLOH% and MSI status were screened in a mct-spheroid assay (tumor cells, endothelial cells, mesenchymal stem cells) with a POLѲ inhibitor, novobiocin, ART-558, and RP6685, alone or in simultaneous combination with a FDA-approved or investigational anticancer small molecule with a 7-day exposure and a CellTiter-Glo 3D luminescence endpoint. As single agents, the POLѲ inhibitors had little or no cytotoxicity. In simultaneous combination with ART-558, talazoparib produced greater-than-additive cytotoxicity at the highest concentrations of the POLѲ inhibitors in the 922,993-354-T-J3-PDC endometrial serous carcinoma mct-spheroids. Activity of the Chk1/2 inhibitor prexasertib was potentiated by either ART-558 or RP6685 in the 922,993-354-T-J3 mct-spheroids. The combination of POLѲ inhibitors ART-558 and RP6685, and the Chk1/2 inhibitor prexasertib produced up to 1 log increase in cytotoxicity in the 922,993-354-T-J3 mct-spheroids. Regions of potentiation were evident in the 922,993-354-T-J3-PDC endometrial carcinoma survival surface plots at the highest concentration of paclitaxel tested, while regions of potentiation were evident in the paclitaxel mid-concentrations of the 299,254-011-R-J1-PDC melanoma mct-spheroids survival surface plots as determined by the Bliss independence calculation. DNA POLѲ is recruited to DNA double-strand breaks as a component of repair. POLѲ allosteric inhibitors, novobiocin, ART558 and RP-6685, have entered clinical trial. The current study explores the cytotoxicity of POLѲ inhibitors in combination with anticancer drugs and investigational agents in patient-derived cell lines grown as mct-spheroids.
新生霉素最近被确定为一种DNA聚合酶Ѳ抑制剂，20世纪80年代末和90年代初，人们在肿瘤细胞、荷瘤小鼠以及与环磷酰胺或顺铂联合进行的1期临床试验中探索了其增强癌症化疗的潜力。已经阐明了可能增加或降低聚合酶Ѳ抑制剂作用的基因改变。在一种多细胞球状体试验（肿瘤细胞、内皮细胞、间充质干细胞）中，对30种已知有BRCA、ATM、ATR、聚合酶Ѳ、XRCC1、PALB2、PARP1、LIG3改变以及已知基因组杂合性缺失（gLOH）百分比和微卫星不稳定性（MSI）状态的患者来源的肿瘤细胞系进行了筛选，试验使用了聚合酶Ѳ抑制剂新生霉素、ART - 558和RP6685，单独使用或与一种FDA批准的或正在研究的抗癌小分子同时联合使用，暴露7天，并以CellTiter - Glo 3D发光作为终点。作为单一药物，聚合酶Ѳ抑制剂几乎没有或没有细胞毒性。在922,993 - 354 - T - J3 - PDC子宫内膜浆液性癌多细胞球状体中，当聚合酶Ѳ抑制剂浓度最高时，与ART - 558同时联合使用，他拉唑帕尼产生了大于相加的细胞毒性。在922,993 - 354 - T - J3多细胞球状体中，Chk1/2抑制剂普瑞赛替尼的活性被ART - 558或RP6685增强。聚合酶Ѳ抑制剂ART - 558和RP6685与Chk1/2抑制剂普瑞赛替尼的联合使用在922,993 - 354 - T - J3多细胞球状体中使细胞毒性增加了高达1个对数。在测试的最高紫杉醇浓度下，922,993 - 354 - T - J3 - PDC子宫内膜癌生存表面图中出现了增效区域，而通过布利斯独立性计算确定，在299,254 - 011 - R - J1 - PDC黑色素瘤多细胞球状体生存表面图的紫杉醇中等浓度下也出现了增效区域。DNA聚合酶Ѳ作为修复的一个组成部分被招募到DNA双链断裂处。聚合酶Ѳ变构抑制剂新生霉素、ART558和RP - 6685已进入临床试验。当前的研究探索了聚合酶Ѳ抑制剂与抗癌药物和研究药物在以多细胞球状体形式生长的患者来源细胞系中的细胞毒性。
