Zhao Qianqian, Kohut Adrian, Li Yi-Jia, Martincuks Antons, Austria Theresa, Zhang Chunyan, Santiago Nicole Lugo, Borrero Rosemarie Martinez, Phan Xuan Thuy, Melstrom Laleh, Rodriguez-Rodriguez Lorna, Yu Hua
Department of Immuno-Oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, United States.
Irell and Manella Graduate School of Biological Sciences, City of Hope National Medical Center, Duarte, CA, United States.
Front Oncol. 2022 Oct 17;12:966492. doi: 10.3389/fonc.2022.966492. eCollection 2022.
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.
最近，聚（ADP - 核糖基）化聚合酶抑制剂（PARP抑制剂），可诱导具有DNA损伤修复缺陷的肿瘤细胞发生合成致死，已成为治疗卵巢癌、乳腺癌和胰腺癌的一种有前景的疗法。尽管PARP抑制剂奥拉帕利仅限于治疗具有DNA修复缺陷的癌症患者，但PARP抑制剂尼拉帕利已获美国食品药品监督管理局（FDA）批准，可用于治疗卵巢癌患者，无论其DNA修复途径的状态如何。尽管对PARP酶的亲和力存在差异，但尼拉帕利在无DNA修复缺陷患者中临床应用的基本原理仍不明确。此外，只有奥拉帕利已被批准用于治疗具有BRCA突变的胰腺导管腺癌（PDAC）患者，而这仅占总PDAC患者的5 - 7%。尼拉帕利对无BRCA突变的PDAC患者是否有益仍不清楚。我们发现，无论BRCA突变状态如何，尼拉帕利抑制卵巢癌和PDAC肿瘤细胞生长的效果都比奥拉帕利更有效。与已知可激活STAT3的奥拉帕利不同，尼拉帕利在卵巢癌和PDAC癌细胞系及患者肿瘤中抑制STAT3活性。此外，尼拉帕利调节参与细胞凋亡的几个STAT3下游基因的表达。组成型激活的STAT3突变体的过表达可挽救尼拉帕利诱导的癌细胞凋亡。我们的结果表明，尼拉帕利通过干扰SRC酪氨酸激酶来抑制磷酸化STAT3（pSTAT3）。总的来说，我们的研究提供了尼拉帕利在无BRCA突变情况下诱导肿瘤细胞凋亡能力的潜在机制，表明尼拉帕利无论BRCA状态如何都有治疗PDAC患者的潜力。
