GLI2-dependent c-MYC upregulation mediates resistance of pancreatic cancer cells to the BET bromodomain inhibitor JQ1.
GLI2-dependent c-MYC upregulation mediates resistance of pancreatic cancer cells to the BET bromodomain inhibitor JQ1.
复制标题
DOI：
10.1038/srep09489
复制
发表时间：
2015-03-25
影响因子：
4.6
通讯作者：
Munshi HG
中科院分区：
文献类型：
--
作者：
Kumar K;Raza SS;Knab LM;Chow CR;Kwok B;Bentrem DJ;Popovic R;Ebine K;Licht JD;Munshi HG
JQ 1和I-BET 151是BET布罗莫结构域蛋白的选择性抑制剂，其对许多不同的癌症具有功效。由于靶向治疗的有效性通常受到耐药性发展的限制，我们检查了癌细胞是否可能对BET抑制剂JQ 1产生耐药性。在这里，我们发现胰腺癌细胞对JQ 1产生耐药性，表现出对I-BET 151的交叉耐药性和对BRD 4下调的不敏感性。耐药细胞维持c-MYC的表达，增加JQ 1靶基因FOSL 1和HMGA 2的表达，并显示上皮-间充质转化（EMT）的证据。然而，逆转EMT不能使抗性细胞对JQ 1处理敏感。重要的是，JQ 1耐药细胞仍然依赖于c-MYC，而c-MYC现在受到高水平GLI 2的共同调节。此外，下调GLI 2使耐药细胞对JQ 1重新敏感。总的来说，这些结果确定了癌细胞对BET抑制剂产生耐药性的机制。
JQ1 and I-BET151 are selective inhibitors of BET bromodomain proteins that have efficacy against a number of different cancers. Since the effectiveness of targeted therapies is often limited by development of resistance, we examined whether it was possible for cancer cells to develop resistance to the BET inhibitor JQ1. Here we show that pancreatic cancer cells developing resistance to JQ1 demonstrate cross-resistance to I-BET151 and insensitivity to BRD4 downregulation. The resistant cells maintain expression of c-MYC, increase expression of JQ1-target genes FOSL1 and HMGA2, and demonstrate evidence of epithelial-mesenchymal transition (EMT). However, reverting EMT fails to sensitize the resistant cells to JQ1 treatment. Importantly, the JQ1-resistant cells remain dependent on c-MYC that now becomes co-regulated by high levels of GLI2. Furthermore, downregulating GLI2 re-sensitizes the resistant cells to JQ1. Overall, these results identify a mechanism by which cancer cells develop resistance to BET inhibitors.
登录
查看更多内容
选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.8
作者：
De Raedt, Thomas;Beert, Eline;Cichowski, Karen
通讯作者：
Cichowski, Karen
影响因子：
4.8
作者：
Dangi-Garimella, Surabhi;Redig, Amanda J.;Munshi, Hidayatullah G.
通讯作者：
Munshi, Hidayatullah G.
影响因子：
64.5
作者：
Delmore JE;Issa GC;Lemieux ME;Rahl PB;Shi J;Jacobs HM;Kastritis E;Gilpatrick T;Paranal RM;Qi J;Chesi M;Schinzel AC;McKeown MR;Heffernan TP;Vakoc CR;Bergsagel PL;Ghobrial IM;Richardson PG;Young RA;Hahn WC;Anderson KC;Kung AL;Bradner JE;Mitsiades CS
通讯作者：
Mitsiades CS
DOI：
10.1073/pnas.1422165112
发表时间：
2015-01-06
影响因子：
11.1
作者：
Baratta, Maria Giuseppina;Schinzel, Anna C.;Livingston, David M.
通讯作者：
Livingston, David M.