PARP Inhibitor Activity Correlates with SLFN11 Expression and Demonstrates Synergy with Temozolomide in Small Cell Lung Cancer.
PARP Inhibitor Activity Correlates with SLFN11 Expression and Demonstrates Synergy with Temozolomide in Small Cell Lung Cancer.
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DOI：
10.1158/1078-0432.ccr-16-1040
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发表时间：
2017-01-15
期刊：
影响因子：
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通讯作者：
Rudin CM
中科院分区：
文献类型：
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作者：
Lok BH;Gardner EE;Schneeberger VE;Ni A;Desmeules P;Rekhtman N;de Stanchina E;Teicher BA;Riaz N;Powell SN;Poirier JT;Rudin CM
PARP抑制剂（PARPi）是一类新型的小分子治疗小细胞肺癌（SCLC）。识别反应的预测因子将促进我们对这种治疗策略的理解，并指导临床应用。使用公共数据集分析PARP抑制剂奥拉帕尼、鲁卡帕尼和维利帕尼以及依托泊苷和顺铂在SCLC细胞系中的功效以及基因表达相关性。HRD基因组瘢痕评分由AffyssSNP 6.0阵列计算。通过细胞活力测定来测量体外他拉唑帕尼功效。对于功能研究，CRISPR-Cas9和shRNA分别用于基因组编辑和转录物敲低。通过免疫印迹和免疫组织化学（IHC）评估蛋白水平。体外测定他拉唑帕尼和替莫唑胺的定量协同作用。在患者来源的异种移植物（PDX）模型中评估他拉唑帕尼、替莫唑胺和组合的体内功效。我们鉴定了SLFN 11，而不是HRD基因组瘢痕，作为对所有三种评估的PARPi的反应的一致相关性，SLFN 11的丧失赋予对PARPi的抗性。我们在体内多次PDX中证实了这些发现，并将SLFN 11的IHC染色定义为talazoparib反应的预测因子。由于替莫唑胺在SCLC中具有活性，我们研究了与talazoparib的联合治疗，发现了显著的体外协同作用和体内疗效，这不仅仅取决于SLFN 11或MGMT状态。SLFN 11是SCLC对PARP抑制剂单药治疗敏感性的相关预测生物标志物，我们将TMZ联合治疗确定为特别有前途的治疗策略，值得进一步临床研究。
PARP inhibitors (PARPi) are a novel class of small molecule therapeutics for small cell lung cancer (SCLC). Identification of predictors of response would advance our understanding, and guide clinical application, of this therapeutic strategy. Efficacy of PARP inhibitors olaparib, rucaparib, and veliparib, as well as etoposide and cisplatin in SCLC cell lines, and gene expression correlates, were analyzed using public datasets. HRD genomic scar scores were calculated from Affymetrix SNP 6.0 arrays. In vitro talazoparib efficacy was measured by cell viability assays. For functional studies, CRISPR-Cas9 and shRNA were used for genomic editing and transcript knockdown, respectively. Protein levels were assessed by immunoblotting and immunohistochemistry (IHC). Quantitative synergy of talazoparib and temozolomide were determined in vitro. In vivo efficacy of talazoparib, temozolomide, and the combination was assessed in patient-derived xenograft (PDX) models. We identified SLFN11, but not HRD genomic scars, as a consistent correlate of response to all three PARPi assessed, with loss of SLFN11 conferring resistance to PARPi. We confirmed these findings in vivo across multiple PDX and defined IHC staining for SLFN11 as a predictor of talazoparib response. As temozolomide has activity in SCLC, we investigated combination therapy with talazoparib and found marked synergy in vitro and efficacy in vivo, which did not solely depend on SLFN11 or MGMT status. SLFN11 is a relevant predictive biomarker of sensitivity to PARP inhibitor monotherapy in SCLC and we identify combinatorial therapy with TMZ as a particularly promising therapeutic strategy that warrants further clinical investigation.