PARP inhibitors (PARPis) display single-agent anticancer activity in small cell lung cancer (SCLC) and other neuroendocrine tumors independent of BRCA1/2 mutations. Here, we determine the differential efficacy of multiple clinical PARPis in SCLC cells. Compared with the other PARPis rucaparib, olaparib, and niraparib, talazoparib displays the highest potency across SCLC, including SLFN11-negative cells. Chemical proteomics identifies PARP16 as a unique talazoparib target in addition to PARP1. Silencing PARP16 significantly reduces cell survival, particularly in combination with PARP1 inhibition. Drug combination screening reveals talazoparib synergy with the WEE1/PLK1 inhibitor adavosertib. Global phosphoproteomics identifies disparate effects on cell-cycle and DNA damage signaling thereby illustrating underlying mechanisms of synergy, which is more pronounced for talazoparib than olaparib. Notably, silencing PARP16 further reduces cell survival in combination with olaparib and adavosertib. Together, these data suggest that PARP16 contributes to talazoparib's overall mechanism of action and constitutes an actionable target in SCLC.

PARP 抑制剂 (PARPis) 在小细胞肺癌 (SCLC) 和其他独立于BRCA1/2突变的神经内分泌肿瘤中表现出单药抗癌活性。在这里，我们确定了多种临床 PARPis 在 SCLC 细胞中的不同功效。与其他 PARPis rucaparib、olaparib 和 niraparib 相比，talazoparib 在 SCLC（包括 SLFN11 阴性细胞）中显示出最高的效力。化学蛋白质组学将 PARP16 鉴定为除 PARP1 之外的独特 talazoparib 靶标。沉默PARP16显着降低细胞存活率，特别是与 PARP1 抑制结合使用。药物组合筛选揭示了 talazoparib 与 WEE1/PLK1 抑制剂 adavosertib 的协同作用。全球磷酸化蛋白质组学确定了对细胞周期和 DNA 损伤信号的不同影响，从而说明了协同作用的潜在机制，talazoparib 比 olaparib 更明显。值得注意的是，与 olaparib 和 adavosertib 联合使用时，沉默PARP16会进一步降低细胞存活率。总之，这些数据表明 PARP16 有助于 talazoparib 的整体作用机制，并构成 SCLC 中的一个可操作靶点。