DataSheet_1_The MYC Paralog-PARP1 Axis as a Potential Therapeutic Target in MYC Paralog-Activated Small Cell Lung Cancer.pdf

Poly (ADP-ribose) polymerase 1 (PARP1) is highly expressed in small cell lung cancer (SCLC) and has emerged as an attractive target for treatment of SCLC. However, the clinical significance of PARP1 expression in SCLC remains elusive. In this study, we showed that high PARP1 expression was associated with better overall survival (OS), and was positively correlated with the expression of MYC paralogs in patients with SCLC. We demonstrated that PARP1 was transcriptionally regulated by MYC paralogs. Integrative analysis of multiple RNA-seq data sets indicated that DNA damage response (DDR) genes involved in the replication stress response (RSR) and homologous recombination (HR) repair pathways were highly enriched in MYC paralog-addicted SCLC cell models and in human SCLC specimens. Targeting the MYC paralog-PARP1 axis with concomitant BET and PARP inhibition resulted in synergistic effects in MYC paralog-activated SCLC. Our study identified a critical PARP1 regulatory pathway, and provided evidence for a rational combination treatment strategy for MYC paralog-activated SCLC.

聚腺苷二磷酸核糖聚合酶1（Poly (ADP-ribose) polymerase 1，PARP1）在小细胞肺癌（small cell lung cancer，SCLC）中呈高表达，已成为SCLC治疗的极具潜力的靶点。然而，PARP1在SCLC中的临床意义仍未明确。本研究发现，高PARP1表达与更好的总生存期（overall survival，OS）相关，且与SCLC患者体内的MYC旁系同源基因（MYC paralogs）表达呈正相关。研究证实，MYC旁系同源基因可在转录水平调控PARP1。对多组RNA测序数据集的整合分析显示，参与复制应激应答（replication stress response，RSR）和同源重组（homologous recombination，HR）修复通路的DNA损伤应答（DNA damage response，DDR）基因，在依赖MYC旁系同源基因的SCLC细胞模型及人类SCLC标本中显著富集。联合靶向MYC旁系同源基因-PARP1轴的BET抑制与PARP抑制，可在MYC旁系同源基因激活的SCLC中产生协同效应。本研究明确了一条关键的PARP1调控通路，并为MYC旁系同源基因激活型SCLC的合理联合治疗策略提供了依据。