Gajan Ambikai, Sarma Ashapurna, Kim Seongho, Gurdziel Katherine, Wu Gen Sheng, Shekhar Malathy P
Karmanos Cancer Institute, Detroit, MI, United States.
Department of Oncology, Wayne State University School of Medicine, Detroit, MI, United States.
Front Oncol. 2021 Jul 22;11:694793. doi: 10.3389/fonc.2021.694793. eCollection 2021.
Poly-(ADP)-ribose polymerase inhibitors (PARPi) and platinum-based drugs are promising therapies for triple negative breast cancers (TNBC) with or loss. PARPi(s) show better efficacies when combined with platinum-based therapy, however, acquisition of PARPi resistance has been linked with co-resistance to platinum-based drugs. Here, we show that TNBCs with constitutively hyperactivated PARP-1 display greater tolerances for the PARPi olaparib and cisplatin, and respond synergistically to olaparib/cisplatin combinations with increased cytotoxicity. Regardless of and PARP-1 activity status, upon gaining olaparib resistance (OlaR), OlaR MDA-MB-468 ( wild-type) and SUM1315 ( mutant) TNBC cells retain cisplatin sensitivities of their isogenic parental counterparts. OlaR TNBC cells express decreased levels of PARP-1 and Pol η, a translesion-synthesis polymerase important in platinum-induced interstrand crosslink repair. Although native RAD51 recombinase levels are unaffected, anti-RAD51 immunoreactive low molecular weight sbands are exclusively detected in OlaR cells. Despite normal , RAD51 foci formation/recruitment to double-strand breaks are impaired in OlaR MDA-MB-468 cells, suggesting homologous-recombination impairment. RNA-seq and pathway analysis of cisplatin-affected genes revealed enrichment of G2/M cell cycle regulation and DNA repair pathways in parental and OlaR MDA-MB-468 cells whereas parental and OlaR SUM1315 cells showed enrichment of inflammatory stress response pathways associated with TNFR1/2, TWEAK and IL-17 signaling. These data show that TNBC models with wild type versus mutant exhibit differences in CDDP-induced cellular response pathways, however, the CDDP-induced signaling responses remain stable across the isogenic models of OlaR from the same lineage. These data also show that adaptive OlaR does not automatically promote cisplatin resistance, implicating the potential benefit of platinum-based therapy for OlaR TNBCs.
聚（ADP）-核糖聚合酶抑制剂（PARPi）和铂类药物是治疗具有BRCA1或BRCA2缺失的三阴性乳腺癌（TNBC）的有前景的疗法。PARPi与铂类疗法联合使用时显示出更好的疗效，然而，获得PARPi耐药性与对铂类药物的共同耐药性有关。在这里，我们表明，PARP-1组成型过度激活的TNBC对PARPi奥拉帕利和顺铂具有更高的耐受性，并对奥拉帕利/顺铂联合用药产生协同反应，细胞毒性增加。无论BRCA状态和PARP-1活性如何，在获得奥拉帕利耐药性（OlaR）后，OlaR MDA-MB-468（野生型）和SUM1315（突变型）TNBC细胞保持其同基因亲本对应物的顺铂敏感性。OlaR TNBC细胞中PARP-1和Pol η的表达水平降低，Pol η是一种在铂诱导的链间交联修复中起重要作用的跨损伤合成聚合酶。尽管天然RAD51重组酶水平未受影响，但在OlaR细胞中仅检测到抗RAD51免疫反应性低分子量条带。尽管BRCA状态正常，但OlaR MDA-MB-468细胞中RAD51焦点形成/募集到双链断裂的过程受损，提示同源重组受损。对顺铂影响的基因进行RNA测序和通路分析发现，亲本和OlaR MDA-MB-468细胞中G2/M细胞周期调控和DNA修复通路富集，而亲本和OlaR SUM1315细胞显示与TNFR1/2、TWEAK和IL-17信号相关的炎症应激反应通路富集。这些数据表明，具有野生型与突变型BRCA的TNBC模型在顺铂诱导的细胞反应通路中存在差异，然而，顺铂诱导的信号反应在来自同一谱系的OlaR同基因模型中保持稳定。这些数据还表明，适应性OlaR不会自动促进顺铂耐药性，这意味着铂类疗法对OlaR TNBCs可能有益。
