Hedgehog/GLI1 Transcriptionally Regulates FANCD2 in Ovarian Tumor Cells: Its Inhibition Induces HR-Deficiency and Synergistic Lethality with PARP Inhibition.
Hedgehog/GLI1 Transcriptionally Regulates FANCD2 in Ovarian Tumor Cells: Its Inhibition Induces HR-Deficiency and Synergistic Lethality with PARP Inhibition.
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Hedgehog/GLI 1转录调节卵巢肿瘤细胞中的FANCD 2：其抑制诱导HR缺陷和与PARP抑制的协同致死性。
DOI：
10.1016/j.neo.2021.06.010
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发表时间：
2021-09
期刊：
影响因子：
--
通讯作者：
Palle K
中科院分区：
文献类型：
--
作者：
Mani C;Tripathi K;Chaudhary S;Somasagara RR;Rocconi RP;Crasto C;Reedy M;Athar M;Palle K
卵巢癌（OC）是女性中最致命的癌症类型之一，由于缺乏有效的靶向治疗以及高的治疗抗性和疾病复发率。最近，聚（ADP-核糖）聚合酶抑制剂（PARPi）已显示出作为化疗药物的前景;然而，它们的疗效仅限于一小部分BRCA突变患者。在这里，我们显示了一个新的功能刺猬（Hh）转录因子胶质瘤相关蛋白1（GLI 1）在调控关键范可尼贫血（FA）基因，FANCD 2在OC细胞。当与PARP抑制组合时，HR-熟练OC细胞中的GLI 1抑制诱导HR缺陷（BRCAness）、复制应激和协同致死。用GLI 1和PARP抑制剂的组合处理OC细胞显示出增强的DNA损伤、细胞毒性的协同作用和强的体内抗癌应答。
Ovarian cancer (OC) is one of the most lethal type of cancer in women due to a lack of effective targeted therapies and high rates of treatment resistance and disease recurrence. Recently Poly (ADP-ribose) polymerase inhibitors (PARPi) have shown promise as chemotherapeutic agents; however, their efficacy is limited to a small fraction of patients with BRCA mutations. Here we show a novel function for the Hedgehog (Hh) transcription factor Glioma associated protein 1 (GLI1) in regulation of key Fanconi anemia (FA) gene, FANCD2 in OC cells. GLI1 inhibition in HR-proficient OC cells induces HR deficiency (BRCAness), replication stress and synergistic lethality when combined with PARP inhibition. Treatment of OC cells with combination of GLI1 and PARP inhibitors shows enhanced DNA damage, synergy in cytotoxicity, and strong in vivo anticancer responses.
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影响因子：
--
作者：
Clark DW;Tripathi K;Dorsman JC;Palle K
通讯作者：
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