A new vulnerability to BET inhibition due to enhanced autophagy in BRCA2 deficient pancreatic cancer.
A new vulnerability to BET inhibition due to enhanced autophagy in BRCA2 deficient pancreatic cancer.
复制标题
BRCA2 缺陷型胰腺癌中自噬增强导致 BET 抑制的新脆弱性。
DOI：
10.1038/s41419-023-06145-9
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发表时间：
2023-09-21
影响因子：
9
通讯作者：
Hwang, Chang-Il
中科院分区：
文献类型：
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作者：
Lee, Eunjung;Archasappawat, Suyakarn;Ji, Keely;Pena, Jocelyn;Fernandez-Vega, Virneliz;Gangaraju, Ritika;Beesabathuni, Nitin Sai;Kim, Martin Jean;Tian, Qi;Shah, Priya S.;Scampavia, Louis;Spicer, Timothy P.;Hwang, Chang-Il
胰腺癌是人类恶性肿瘤中最致命的疾病之一。在全部胰腺癌患者中，约10%的患者被归类为家族性胰腺癌(FPC)患者，携带与DNA修复途径有关的基因的胚系突变(如BRCA2)。针对患者突变量身定做的个性化药物方法将改善患者的预后。为了确定BRCA2缺陷的胰腺癌新的易感性，我们建立了同基因BRCA2缺陷的小鼠胰腺癌细胞系，并进行了高通量药物筛选。高通量药物筛选显示BRCA2缺陷细胞对溴域和端外基序(BET)抑制剂敏感，提示抑制BET可能是一种潜在的治疗方法。我们发现BRCA2缺乏增加了自噬通量，在BRCA2缺乏的胰腺癌细胞中抑制BET进一步增强了自噬通量，导致自噬依赖的细胞死亡。我们的数据表明，抑制BET可以成为BRCA2缺陷的胰腺癌的一种新的治疗策略。
Pancreatic cancer is one of the deadliest diseases in human malignancies. Among total pancreatic cancer patients, ~10% of patients are categorized as familial pancreatic cancer (FPC) patients, carrying germline mutations of the genes involved in DNA repair pathways (e.g., BRCA2). Personalized medicine approaches tailored toward patients’ mutations would improve patients’ outcome. To identify novel vulnerabilities of BRCA2-deficient pancreatic cancer, we generated isogenic Brca2-deficient murine pancreatic cancer cell lines and performed high-throughput drug screens. High-throughput drug screening revealed that Brca2-deficient cells are sensitive to Bromodomain and Extraterminal Motif (BET) inhibitors, suggesting that BET inhibition might be a potential therapeutic approach. We found that BRCA2 deficiency increased autophagic flux, which was further enhanced by BET inhibition in Brca2-deficient pancreatic cancer cells, resulting in autophagy-dependent cell death. Our data suggests that BET inhibition can be a novel therapeutic strategy for BRCA2-deficient pancreatic cancer.
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