DataSheet_1_Niraparib-induced STAT3 inhibition increases its antitumor effects.pdf

Recently, poly(ADP-ribosyl)ation polymerase inhibitors (PARPis), which induce synthetic lethality of tumor cells with DNA damage repair defects, have emerged as a promising therapy for ovarian, breast, and pancreatic cancer. Although the PARPi Olaparib is limited to treating cancer patients with DNA repair deficiencies, the PARPi Niraparib is FDA approved to treat ovarian cancer patients regardless of their status in DNA repair pathways. Despite differences in the affinity to PARP enzymes, the rationale behind the clinical use of Niraparib in patients without DNA repair deficiencies is still lacking. Moreover, only Olaparib has been approved for pancreatic ductal adenocarcinoma (PDAC) patients with BRCA mutations, accounting for only 5-7% of total PDACs. It remains unclear whether Niraparib could be beneficial to PDACs without BRCA mutations. We found that Niraparib inhibits ovarian and PDAC tumor cell growth, regardless of BRCA mutational status, more effectively than Olaparib. Unlike Olaparib, which is known to activate STAT3, Niraparib inhibits STAT3 activity in ovarian and PDAC cancer cell lines and patient tumors. Moreover, Niraparib regulates the expression of several STAT3 downstream genes involved in apoptosis. Overexpression of a constitutively activated STAT3 mutant rescues Niraparib-induced cancer cell apoptosis. Our results suggest that Niraparib inhibits pSTAT3 by interfering with SRC tyrosine kinase. Collectively, our studies provide a mechanism underlying Niraparib’s ability to induce tumor cell apoptosis without BRCA mutations, suggesting the potential use of Niraparib for treating PDAC patients regardless of BRCA status.

近年来，诱导携带DNA损伤修复缺陷的肿瘤细胞发生合成致死的聚ADP核糖聚合酶抑制剂（poly(ADP-ribosyl)ation polymerase inhibitors, PARPis）已成为卵巢癌、乳腺癌及胰腺癌的颇具前景的治疗手段。尽管PARPi奥拉帕利（Olaparib）仅被批准用于治疗存在DNA修复缺陷的癌症患者，但PARPi尼拉帕利（Niraparib）已获美国食品药品监督管理局（FDA）批准，可用于无论DNA修复通路状态如何的卵巢癌患者。尽管二者与PARP酶的结合亲和力存在差异，但尼拉帕利在无DNA修复缺陷患者中的临床应用理论基础仍不明确。此外，目前仅奥拉帕利被批准用于携带BRCA突变的胰腺导管腺癌（pancreatic ductal adenocarcinoma, PDAC）患者，而此类患者仅占全部PDAC病例的5%~7%。目前仍不清楚尼拉帕利是否对无BRCA突变的PDAC患者具有治疗获益。我们发现，无论BRCA突变状态如何，尼拉帕利均较奥拉帕利更有效地抑制卵巢癌及PDAC肿瘤细胞的增殖。与已知可激活信号转导与转录激活因子3（Signal Transducer and Activator of Transcription 3, STAT3）的奥拉帕利不同，尼拉帕利可在卵巢癌、PDAC细胞系及患者肿瘤组织中抑制STAT3的活性。此外，尼拉帕利可调控多个参与细胞凋亡过程的STAT3下游基因的表达。组成型激活的STAT3突变体的过表达可逆转尼拉帕利诱导的肿瘤细胞凋亡。我们的研究结果表明，尼拉帕利通过干扰Src酪氨酸激酶（SRC tyrosine kinase）的活性抑制磷酸化STAT3（pSTAT3）的水平。综上，本研究阐明了尼拉帕利在不依赖BRCA突变的情况下诱导肿瘤细胞凋亡的潜在分子机制，提示尼拉帕利有望用于无论BRCA状态如何的PDAC患者的治疗。