Dasatinib induces DNA damage and activates DNA repair pathways leading to senescence in non-small cell lung cancer cell lines with kinase-inactivating BRAF mutations.
Dasatinib induces DNA damage and activates DNA repair pathways leading to senescence in non-small cell lung cancer cell lines with kinase-inactivating BRAF mutations.
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DOI：
10.18632/oncotarget.6376
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发表时间：
2016-01-05
期刊：
影响因子：
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通讯作者：
Johnson FM
中科院分区：
文献类型：
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作者：
Peng S;Sen B;Mazumdar T;Byers LA;Diao L;Wang J;Tong P;Giri U;Heymach JV;Kadara HN;Johnson FM
非小细胞肺癌（NSCLC）不携带靶向激酶突变或易位，非常需要改进的治疗方法。我们以前证明，当用多靶点激酶抑制剂达沙替尼治疗时，携带激酶失活BRAF突变（KIBRAF）的NSCLC细胞会发生衰老。同样，达沙替尼治疗在KIBRAF NSCLC患者中产生了深刻而持久的缓解。然而，没有典型的途径解释达沙替尼诱导的KIBRAF NSCLC衰老。为了研究潜在的机制，我们使用了两种方法：基因表达和反相蛋白阵列。这两种方法都表明，DNA修复途径在KIBRAF NSCLC细胞和野生型（WT）BRAF细胞之间存在差异。与这些发现一致，达沙替尼仅在KIBRAF细胞中诱导DNA损伤并激活DNA修复途径，导致衰老。此外，达沙替尼诱导的衰老依赖于Chk1和p21，这两种蛋白质已知介导DNA损伤诱导的衰老。达沙替尼还导致TAZ蛋白水平显著降低，但雅普蛋白水平未显著降低。TAZ的过表达抑制达沙替尼诱导的衰老。为了研究KIBRAF NSCLC细胞的其他脆弱性，我们比较了这些细胞与WTBRAF NSCLC细胞对79种药物的敏感性，并确定了KIBRAF细胞对EGFR和MEK抑制剂的敏感性模式。临床批准的EGFR和MEK抑制剂，比达沙替尼耐受性更好，可用于治疗KIBRAF NSCLC。我们的新发现，达沙替尼诱导DNA损伤，随后激活DNA修复途径，导致KIBRAF NSCLC细胞衰老，这代表了具有潜在临床应用的独特脆弱性。
Improved therapies are greatly needed for non-small cell lung cancer (NSCLC) that does not harbor targetable kinase mutations or translocations. We previously demonstrated that NSCLC cells that harbor kinase-inactivating BRAF mutations (KIBRAF) undergo senescence when treated with the multitargeted kinase inhibitor dasatinib. Similarly, treatment with dasatinib resulted in a profound and durable response in a patient with KIBRAF NSCLC. However, no canonical pathways explain dasatinib-induced senescence in KIBRAF NSCLC. To investigate the underlying mechanism, we used 2 approaches: gene expression and reverse phase protein arrays. Both approaches showed that DNA repair pathways were differentially modulated between KIBRAF NSCLC cells and those with wild-type (WT) BRAF. Consistent with these findings, dasatinib induced DNA damage and activated DNA repair pathways leading to senescence only in the KIBRAF cells. Moreover, dasatinib-induced senescence was dependent on Chk1 and p21, proteins known to mediate DNA damage-induced senescence. Dasatinib also led to a marked decrease in TAZ but not YAP protein levels. Overexpression of TAZ inhibited dasatinib-induced senescence. To investigate other vulnerabilities in KIBRAF NSCLC cells, we compared the sensitivity of these cells with that of WTBRAF NSCLC cells to 79 drugs and identified a pattern of sensitivity to EGFR and MEK inhibitors in the KIBRAF cells. Clinically approved EGFR and MEK inhibitors, which are better tolerated than dasatinib, could be used to treat KIBRAF NSCLC. Our novel finding that dasatinib induced DNA damage and subsequently activated DNA repair pathways leading to senescence in KIBRAF NSCLC cells represents a unique vulnerability with potential clinical applications.