Niraparib-induced STAT3 inhibition increases its antitumor effects.
Niraparib-induced STAT3 inhibition increases its antitumor effects.
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DOI：
10.3389/fonc.2022.966492
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发表时间：
2022
影响因子：
4.7
通讯作者：
Yu, Hua
中科院分区：
文献类型：
--
作者：
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
最近，聚(ADP-核糖基)聚合酶抑制剂(PARPis)可以诱导具有DNA损伤修复缺陷的肿瘤细胞的合成杀伤力，已成为卵巢癌、乳腺癌和胰腺癌的一种有前途的治疗方法。尽管PARPI Olararib仅限于治疗有DNA修复缺陷的癌症患者，但PARPI Niraparib已被FDA批准用于治疗卵巢癌患者，无论他们在DNA修复途径中处于何种状态。尽管对PARP酶的亲和力不同，但在没有DNA修复缺陷的患者中临床使用Niraparib的理由仍然缺乏。此外，只有奥拉帕利被批准用于BRCA突变的胰腺导管腺癌(PDAC)患者，仅占PDAC总数的5-7%。目前尚不清楚Niraparib是否对没有BRCA突变的PDAC有益。我们发现，Niraparib抑制卵巢和PDAC肿瘤细胞的生长，无论BRCA突变状态如何，都比奥拉帕利更有效。与已知可以激活STAT3的奥拉帕利布不同，Niraparib抑制卵巢和PDAC癌细胞系以及患者肿瘤中的STAT3活性。此外，Niraparib还调节几个与细胞凋亡有关的STAT3下游基因的表达。成分激活的STAT3突变体的过表达挽救了Niraparib诱导的癌细胞凋亡。我们的结果提示Niraparib通过干扰SRC酪氨酸激酶来抑制pSTAT3。总而言之，我们的研究提供了一个潜在的机制，Niraparib能够在没有BRCA突变的情况下诱导肿瘤细胞凋亡，这表明Niraparib可能用于治疗PDAC患者，而无论BRCA状态如何。
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.
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影响因子：
6.2
作者：
Manek, R.;Pakzamir, E.;Lawrenson, K.
通讯作者：
Lawrenson, K.
影响因子：
64.8
作者：
Lee, Jae W.;Stone, Meredith L.;Beatty, Gregory L.
通讯作者：
Beatty, Gregory L.
影响因子：
7.3
作者：
Jones, Philip;Wilcoxen, Keith;Toniatti, Carlo
通讯作者：
Toniatti, Carlo
影响因子：
11.5
作者：
Duan, Zhenfeng;Foster, Rosemary;Seiden, Michael V.
通讯作者：
Seiden, Michael V.
影响因子：
158.5
作者：
Gonzalez-Martin, A.;Pothuri, B.;Monk, B. J.
通讯作者：
Monk, B. J.