KEAP1 loss modulates sensitivity to kinase targeted therapy in lung cancer
KEAP1 loss modulates sensitivity to kinase targeted therapy in lung cancer
复制标题
DOI：
10.7554/elife.18970
复制
发表时间：
2017-02-01
期刊：
影响因子：
7.7
通讯作者：
Hahn, William C.
中科院分区：
文献类型：
--
作者：
Krail, Elsa B.;Wang, Belinda;Hahn, William C.
靶向受体酪氨酸激酶（RTK）/Ras/促分裂原活化蛋白激酶（MAPK）途径的抑制剂已经导致肺癌和其他癌症的临床应答，但是一些患者没有应答，并且在那些应答的患者中不可避免地发生抗性（Balak et al.，2006年; Kobalek等人，2006; Rudin等人，2013; Wagle等人，2011年）。为了了解对MAPK信号传导抑制的内在和获得性抗性，我们在BRAF、MEK、EGFR和ALK抑制的情况下进行了CRISPR-Cas9基因缺失筛选。KEAP 1（NFE 2L 2/NRF 2的负调节因子）的缺失可调节BRAF、NRAS、KRAS、EGFR和ALK突变型肺癌细胞对BRAF、MEK、EGFR和ALK抑制的反应。用靶向RTK/MAPK通路的抑制剂治疗增加了具有完整KEAP 1的细胞中的活性氧（ROS），并且KEAP 1的缺失消除了这种增加。此外，KEAP 1的缺失改变了细胞代谢，使细胞在没有MAPK信号的情况下增殖。这些观察结果表明，KEAP 1/NRF 2通路的改变可能会促进在存在多种针对RTK/Ras/MAPK通路的抑制剂的情况下的存活。
Inhibitors that target the receptor tyrosine kinase (RTK)/Ras/mitogen-activated protein kinase (MAPK) pathway have led to clinical responses in lung and other cancers, but some patients fail to respond and in those that do resistance inevitably occurs (Balak et al., 2006; Kosaka et al., 2006; Rudin et al., 2013; Wagle et al., 2011). To understand intrinsic and acquired resistance to inhibition of MAPK signaling, we performed CRISPR-Cas9 gene deletion screens in the setting of BRAF, MEK, EGFR, and ALK inhibition. Loss of KEAP1, a negative regulator of NFE2L2/NRF2, modulated the response to BRAF, MEK, EGFR, and ALK inhibition in BRAF-, NRAS-, KRAS-, EGFR-, and ALK-mutant lung cancer cells. Treatment with inhibitors targeting the RTK/MAPK pathway increased reactive oxygen species (ROS) in cells with intact KEAP1, and loss of KEAP1 abrogated this increase. In addition, loss of KEAP1 altered cell metabolism to allow cells to proliferate in the absence of MAPK signaling. These observations suggest that alterations in the KEAP1/NRF2 pathway may promote survival in the presence of multiple inhibitors targeting the RTK/Ras/MAPK pathway.