KP372-1-Induced AKT Hyperactivation Blocks DNA Repair to Synergize With PARP Inhibitor Rucaparib via Inhibiting FOXO3a/GADD45α Pathway.
KP372-1-Induced AKT Hyperactivation Blocks DNA Repair to Synergize With PARP Inhibitor Rucaparib via Inhibiting FOXO3a/GADD45α Pathway.
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DOI：
10.3389/fonc.2022.976292
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发表时间：
2022
影响因子：
4.7
通讯作者：
中科院分区：
文献类型：
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聚（ADP-核糖）聚合酶（PARP）抑制剂（PARPi）在同源重组（HR）缺陷的肿瘤治疗中显示出巨大的前景，然而，最终恢复DNA修复和细胞进展的PARPi抗性已成为巨大的临床挑战。最近，KP 372 -1被鉴定为一种新型潜在抗癌剂，其靶向氧化还原酶NAD（P）H：醌氧化还原酶1（NQO 1），以诱导广泛的活性氧（ROS）产生，从而放大DNA损伤，导致癌细胞死亡。为了克服PARPi抗性并扩大其治疗效用，我们研究了亚致死剂量的KP 372 -1与无毒剂量的PARPi rucaparib的组合疗法是否会在NQO 1过表达癌症中协同作用并增强致死率。我们报道了KP 372 -1和rucaparib联合治疗诱导了短暂和显著的AKT超活化，其通过调节FOXO 3a/GADD 45 α通路抑制DNA修复，从而增强PARPi致死性并克服PARPi抗性。我们进一步发现，PARP抑制阻断KP 372 -1诱导的PARP 1超活化，以逆转NAD+/ATP损失，从而促进Ca 2+依赖性自噬和凋亡。此外，用BAPTA-AM（一种胞浆Ca 2+螯合剂）预处理细胞，可显著挽救KP 372 -1或联合处理诱导的致死性，并显著抑制PAR形成和γ H2 AX活化。最后，我们证明了这种联合治疗增强了两种药物在小鼠肿瘤组织中的积累，并协同抑制原位胰腺癌和非小细胞肺癌异种移植模型中的肿瘤生长。总之，我们的研究为NQO 1+实体瘤的新联合治疗提供了新的临床前证据，这可能会扩大PARPi的临床用途。
Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) have exhibited great promise in the treatment of tumors with homologous recombination (HR) deficiency, however, PARPi resistance, which ultimately recovers DNA repair and cell progress, has become an enormous clinical challenge. Recently, KP372-1 was identified as a novel potential anticancer agent that targeted the redox enzyme, NAD(P)H:quinone oxidoreductase 1 (NQO1), to induce extensive reactive oxygen species (ROS) generation that amplified DNA damage, leading to cancer cell death. To overcome PARPi resistance and expand its therapeutic utility, we investigated whether a combination therapy of a sublethal dose of KP372-1 with a nontoxic dose of PARPi rucaparib would synergize and enhance lethality in NQO1 over-expressing cancers. We reported that the combination treatment of KP372-1 and rucaparib induced a transient and dramatic AKT hyperactivation that inhibited DNA repair by regulating FOXO3a/GADD45α pathway, which enhanced PARPi lethality and overcame PARPi resistance. We further found that PARP inhibition blocked KP372-1-induced PARP1 hyperactivation to reverse NAD+/ATP loss that promoted Ca2+-dependent autophagy and apoptosis. Moreover, pretreatment of cells with BAPTA-AM, a cytosolic Ca2+ chelator, dramatically rescued KP372-1- or combination treatment-induced lethality and significantly suppressed PAR formation and γH2AX activation. Finally, we demonstrated that this combination therapy enhanced accumulation of both agents in mouse tumor tissues and synergistically suppressed tumor growth in orthotopic pancreatic and non-small-cell lung cancer xenograft models. Together, our study provides novel preclinical evidence for new combination therapy in NQO1+ solid tumors that may broaden the clinical utility of PARPi.
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过氧化氢酶消除了NQO1阳性乳腺癌中的β-拉帕酮诱导的PARP1过度激活导向的坏死。
影响因子：
5.7
作者：
Bey EA;Reinicke KE;Srougi MC;Varnes M;Anderson VE;Pink JJ;Li LS;Patel M;Cao L;Moore Z;Rommel A;Boatman M;Lewis C;Euhus DM;Bornmann WG;Buchsbaum DJ;Spitz DR;Gao J;Boothman DA
通讯作者：
Boothman DA
影响因子：
50.3
作者：
Huang X;Motea EA;Moore ZR;Yao J;Dong Y;Chakrabarti G;Kilgore JA;Silvers MA;Patidar PL;Cholka A;Fattah F;Cha Y;Anderson GG;Kusko R;Peyton M;Yan J;Xie XJ;Sarode V;Williams NS;Minna JD;Beg M;Gerber DE;Bey EA;Boothman DA
通讯作者：
Boothman DA
FOXO3a 在致癌过程中的关键作用
影响因子：
37.3
作者：
Liu Y;Ao X;Ding W;Ponnusamy M;Wu W;Hao X;Yu W;Wang Y;Li P;Wang J
通讯作者：
Wang J
影响因子：
3.7
作者：
Ethier, Chantal;Tardif, Maxime;Poirier, Guy G.
通讯作者：
Poirier, Guy G.
DOI：
10.1038/nrm.2017.53
发表时间：
2017-10
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Ray Chaudhuri A;Nussenzweig A
通讯作者：
Nussenzweig A