Exploiting interconnected synthetic lethal interactions between PARP inhibition and cancer cell reversible senescence
Exploiting interconnected synthetic lethal interactions between PARP inhibition and cancer cell reversible senescence
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DOI：
10.1038/s41467-019-10460-1
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发表时间：
2019-06-11
影响因子：
16.6
通讯作者：
Rodier, Francis
中科院分区：
文献类型：
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作者：
Fleury, Hubert;Malaquin, Nicolas;Rodier, Francis
衰老是一种以稳定的增殖抑制为特征的肿瘤抑制机制。在这里，我们证明了已知的合成的ADP-核糖聚合酶1抑制剂(PARPI)与DNA修复之间的致死作用触发了P53非依赖的卵巢癌细胞的衰老，其定义与衰老相关的表型特征包括DNA疤痕、炎性分泌体、Bclxl介导的凋亡抵抗以及通过Chk2和p21(CDKN1A)的增殖限制。衰老是不可逆的这一概念仍然存在争议，在这里，我们证明了PARPI-衰老细胞在停药后重新启动增殖，潜在地解释了临床上持续PARPI治疗的必要性。重要的是，PARPI诱导的衰老使卵巢癌细胞和乳腺癌细胞对使用抗衰老药物针对衰老状态的第二阶段合成致死方法瞬时敏感。在卵巢癌和乳腺癌的临床前模型中，PARPI和感觉剂的结合是有效的，这表明将这些合成致死物结合起来提供了一种合理的临床使用方法，联合使用可能在限制耐药性方面更有效。
Senescence is a tumor suppression mechanism defined by stable proliferation arrest. Here we demonstrate that the known synthetic lethal interaction between poly(ADP-ribose) polymerase 1 inhibitors (PARPi) and DNA repair triggers p53-independent ovarian cancer cell senescence defined by senescence-associated phenotypic hallmarks including DNA-SCARS, inflammatory secretome, Bcl-XL-mediated apoptosis resistance, and proliferation restriction via Chk2 and p21 (CDKN1A). The concept of senescence as irreversible remains controversial and here we show that PARPi-senescent cells re-initiate proliferation upon drug withdrawal, potentially explaining the requirement for sustained PARPi therapy in the clinic. Importantly, PARPi-induced senescence renders ovarian and breast cancer cells transiently susceptible to second-phase synthetic lethal approaches targeting the senescence state using senolytic drugs. The combination of PARPi and a senolytic is effective in preclinical models of ovarian and breast cancer suggesting that coupling these synthetic lethalities provides a rational approach to their clinical use and may together be more effective in limiting resistance.