DDX3X induces primary EGFR-TKI resistance based on intratumor heterogeneity in lung cancer cells harboring EGFR-activating mutations.
DDX3X induces primary EGFR-TKI resistance based on intratumor heterogeneity in lung cancer cells harboring EGFR-activating mutations.
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DOI：
10.1371/journal.pone.0111019
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Narita I
中科院分区：
文献类型：
--
作者：
Nozaki K;Kagamu H;Shoji S;Igarashi N;Ohtsubo A;Okajima M;Miura S;Watanabe S;Yoshizawa H;Narita I
携带表皮生长因子受体（EGFR）激活突变的肺癌细胞如何在EGFR-酪氨酸激酶抑制剂（TKI）治疗后存活直至最终获得耐药基因突变的具体机制尚不清楚。由遗传或表观遗传改变（肿瘤内异质性）引起的癌细胞表型多样性导致治疗失败，并可能通过达尔文选择促进肿瘤进化。最近，我们通过蛋白质组分析发现DDX 3X是在具有癌症干细胞（CSC）样表型的小鼠黑素瘤中优先表达的蛋白质。在本研究中，我们用编码DDX 3X的cDNA转染携带EGFR外显子19缺失的人肺癌细胞PC 9，发现DDX 3X，一种ATP依赖性RNA解旋酶，诱导CSC样表型和上皮间质转化（EMT）伴随着对EGFR-TKI的敏感性丧失。DDX 3X表达与Sox 2的上调和表现出CSC样表型的癌细胞的增加相关，如锚定非依赖性增殖、CD 44和醛脱氢酶（ALDH）的强表达。DDX 3X还促进了E-cadherin向N-cadherin转换的EMT。在强表达DDX 3X的肺癌细胞中，配体非依赖性或配体诱导的EGFR磷酸化被抑制。缺乏EGFR信号成瘾导致对EGFR-TKI的耐药性。此外，我们发现了一个小的非粘附亚群，强烈表达DDX 3X伴随着相同的干细胞样特性和EMT在亲本PC 9细胞。独特的亚群缺乏EGFR信号传导，对EGFR-TKI高度耐药。总之，我们的数据表明，DDX 3X可能在诱导表型多样性方面发挥关键作用，靶向DDX 3X的治疗可能克服肿瘤内异质性导致的对EGFR-TKI的原发性耐药。
The specific mechanisms how lung cancer cells harboring epidermal growth factor receptor (EGFR) activating mutations can survive treatment with EGFR-tyrosine kinase inhibitors (TKIs) until they eventually acquire treatment-resistance genetic mutations are unclear. The phenotypic diversity of cancer cells caused by genetic or epigenetic alterations (intratumor heterogeneity) confers treatment failure and may foster tumor evolution through Darwinian selection. Recently, we found DDX3X as the protein that was preferentially expressed in murine melanoma with cancer stem cell (CSC)-like phenotypes by proteome analysis. In this study, we transfected PC9, human lung cancer cells harboring EGFR exon19 deletion, with cDNA encoding DDX3X and found that DDX3X, an ATP-dependent RNA helicase, induced CSC-like phenotypes and the epithelial-mesenchymal transition (EMT) accompanied with loss of sensitivity to EGFR-TKI. DDX3X expression was associated with upregulation of Sox2 and increase of cancer cells exhibiting CSC-like phenotypes, such as anchorage-independent proliferation, strong expression of CD44, and aldehyde dehydrogenase (ALDH). The EMT with switching from E-cadherin to N-cadherin was also facilitated by DDX3X. Either ligand-independent or ligand-induced EGFR phosphorylation was inhibited in lung cancer cells that strongly expressed DDX3X. Lack of EGFR signal addiction resulted in resistance to EGFR-TKI. Moreover, we found a small nonadherent subpopulation that strongly expressed DDX3X accompanied by the same stem cell-like properties and the EMT in parental PC9 cells. The unique subpopulation lacked EGFR signaling and was highly resistant to EGFR-TKI. In conclusion, our data indicate that DDX3X may play a critical role for inducing phenotypic diversity, and that treatment targeting DDX3X may overcome primary resistance to EGFR-TKI resulting from intratumor heterogeneity.
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影响因子：
158.5
作者：
Lynch, TJ;Bell, DW;Haber, DA
通讯作者：
Haber, DA
髓母细胞瘤外观测序发现亚型特异性体细胞突变。
影响因子：
64.8
作者：
Pugh, Trevor J.;Weeraratne, Shyamal Dilhan;Archer, Tenley C.;Krummel, Daniel A. Pomeranz;Auclair, Daniel;Bochicchio, James;Carneiro, Mauricio O.;Carter, Scott L.;Cibulskis, Kristian;Erlich, Rachel L.;Greulich, Heidi;Lawrence, Michael S.;Lennon, Niall J.;McKenna, Aaron;Meldrim, James;Ramos, Alex H.;Ross, Michael G.;Russ, Carsten;Shefler, Erica;Sivachenko, Andrey;Sogoloff, Brian;Stojanov, Petar;Tamayo, Pablo;Mesirov, Jill P.;Amani, Vladimir;Teider, Natalia;Sengupta, Soma;Francois, Jessica Pierre;Northcott, Paul A.;Taylor, Michael D.;Yu, Furong;Crabtree, Gerald R.;Kautzman, Amanda G.;Gabriel, Stacey B.;Getz, Gad;Jaeger, Natalie;Jones, David T. W.;Lichter, Peter;Pfister, Stefan M.;Roberts, Thomas M.;Meyerson, Matthew;Pomeroy, Scott L.;Cho, Yoon-Jae
通讯作者：
Cho, Yoon-Jae
影响因子：
51.1
作者：
Mitsudomi, Tetsuya;Morita, Satoshi;Fukuoka, Masahiro
通讯作者：
Fukuoka, Masahiro
影响因子：
4.3
作者：
Ambrus, Aaron M.;Frolov, Maxim V.
通讯作者：
Frolov, Maxim V.
影响因子：
8
作者：
Botlagunta, M.;Vesuna, F.;Raman, V.
通讯作者：
Raman, V.