Resistance to PARP inhibitors by SLFN11 inactivation can be overcome by ATR inhibition.
Resistance to PARP inhibitors by SLFN11 inactivation can be overcome by ATR inhibition.
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DOI：
10.18632/oncotarget.12266
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发表时间：
2016-11-22
期刊：
影响因子：
--
通讯作者：
Pommier Y
中科院分区：
文献类型：
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作者：
Murai J;Feng Y;Yu GK;Ru Y;Tang SW;Shen Y;Pommier Y
聚（ADP-核糖）聚合酶抑制剂（PARPI）通过捕获PARP 1和PARP 2杀死癌细胞。Talazoparib是最有效的PARPI抑制剂（PARPI），在NCI-60癌细胞系中表现出显著的选择性，超过了BRCA灭活。我们的基因组分析揭示了对talazoparib的响应与Schlafen 11（SLFN 11）表达之间的高度相关性。在四个同基因SLFN 11阳性和阴性细胞系中建立了因果关系，并扩展到奥拉帕尼。对他拉唑帕尼-替莫唑胺组合的反应也由SLFN 11驱动，并在36个小细胞肺癌细胞系和异种移植模型中得到验证。SLFN 11缺陷细胞的耐药性既不是由药物渗透受损也不是由同源重组激活引起的。相反，SLFN 11诱导不可逆的和致命的复制抑制，这是不依赖于ATR介导的S期检查点。通过ATR抑制克服了SLFN 11失活对PARPI的抗性，这在机制上是因为SLFN 11缺陷型细胞在PARPI处理下仅依赖ATR活化来存活。我们的研究表明，SLFN 11失活在癌细胞中很常见（约45%），是PARPI的一种新的主导抗性决定因素。
Poly(ADP-ribose) polymerase inhibitors (PARPIs) kill cancer cells by trapping PARP1 and PARP2. Talazoparib, the most potent PARPI inhibitor (PARPI), exhibits remarkable selectivity among the NCI-60 cancer cell lines beyond BRCA inactivation. Our genomic analyses reveal high correlation between response to talazoparib and Schlafen 11 (SLFN11) expression. Causality was established in four isogenic SLFN11-positive and -negative cell lines and extended to olaparib. Response to the talazoparib-temozolomide combination was also driven by SLFN11 and validated in 36 small cell lung cancer cell lines, and in xenograft models. Resistance in SLFN11-deficient cells was caused neither by impaired drug penetration nor by activation of homologous recombination. Rather, SLFN11 induced irreversible and lethal replication inhibition, which was independent of ATR-mediated S-phase checkpoint. The resistance to PARPIs by SLFN11 inactivation was overcome by ATR inhibition, mechanistically because SLFN11-deficient cells solely rely on ATR activation for their survival under PARPI treatment. Our study reveals that SLFN11 inactivation, which is common (~45%) in cancer cells, is a novel and dominant resistance determinant to PARPIs.