RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer.
RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer.
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DOI：
10.1038/ncomms7377
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发表时间：
2015-03-11
影响因子：
16.6
通讯作者：
Engelman, Jeffrey A.
中科院分区：
文献类型：
--
作者：
Niederst, Matthew J.;Sequist, Lecia V.;Poirier, John T.;Mermel, Craig H.;Lockerman, Elizabeth L.;Garcia, Angel R.;Katayama, Ryohei;Costa, Carlotta;Ross, Kenneth N.;Moran, Teresa;Howe, Emily;Fulton, Linnea E.;Mulvey, Hillary E.;Bernardo, Lindsay A.;Mohamoud, Farhiya;Miyoshi, Norikatsu;VanderLaan, Paul A.;Costa, Daniel B.;Jaenne, Pasi A.;Borger, Darrell R.;Ramaswamy, Sridhar;Shioda, Toshi;Iafrate, Anthony J.;Getz, Gad;Rudin, Charles M.;Mino-Kenudson, Mari;Engelman, Jeffrey A.
酪氨酸激酶抑制剂是治疗表皮生长因子受体（EGFR）突变的非小细胞肺癌（NSCLC）的有效治疗方法。然而，复发通常发生在平均1年的连续治疗后。在耐药癌症的一个子集中观察到从NSCLC到小细胞肺癌（SCLC）的基本组织学转化，但与这种转化相关的分子变化仍然未知。对来自耐药EGFR突变患者的肿瘤样本和细胞系的分析显示，视网膜母细胞瘤（RB）在这些SCLC转化病例中100%丢失，但在保留NSCLC的病例中很少丢失。此外，与耐药NSCLC相比，在耐药SCLC转化的癌症中观察到神经内分泌标志物增加和EGFR表达降低以及对BCL 2家族抑制的更大敏感性。总之，这些发现表明，这种耐药癌症的子集最终采用了经典SCLC的许多分子和表型特征。 对酪氨酸激酶抑制剂的耐药发生在EGFR突变的非小细胞肺癌（NSCLC）的治疗中，但这种获得性耐药的机制尚不清楚。在这里，作者研究了从NSCLC向小细胞肺癌表型转变的耐药癌症中发生的分子变化，并在此过程中涉及视网膜母细胞瘤的丢失。
Tyrosine kinase inhibitors are effective treatments for non-small-cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) mutations. However, relapse typically occurs after an average of 1 year of continuous treatment. A fundamental histological transformation from NSCLC to small-cell lung cancer (SCLC) is observed in a subset of the resistant cancers, but the molecular changes associated with this transformation remain unknown. Analysis of tumour samples and cell lines derived from resistant EGFR mutant patients revealed that Retinoblastoma (RB) is lost in 100% of these SCLC transformed cases, but rarely in those that remain NSCLC. Further, increased neuroendocrine marker and decreased EGFR expression as well as greater sensitivity to BCL2 family inhibition are observed in resistant SCLC transformed cancers compared with resistant NSCLCs. Together, these findings suggest that this subset of resistant cancers ultimately adopt many of the molecular and phenotypic characteristics of classical SCLC. Resistance to tyrosine kinase inhibitors occurs in treatments of non-small-cell lung cancers (NSCLCs) with EGFR mutations but the mechanisms underlying this acquired resistance are unknown. Here the authors examine the molecular changes that occur in resistant cancers that transition from NSCLC to small-cell lung cancer phenotype and implicate loss of retinoblastoma in this process.
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影响因子：
11.2
作者：
Sasaki T;Koivunen J;Ogino A;Yanagita M;Nikiforow S;Zheng W;Lathan C;Marcoux JP;Du J;Okuda K;Capelletti M;Shimamura T;Ercan D;Stumpfova M;Xiao Y;Weremowicz S;Butaney M;Heon S;Wilner K;Christensen JG;Eck MJ;Wong KK;Lindeman N;Gray NS;Rodig SJ;Jänne PA
通讯作者：
Jänne PA
影响因子：
64.8
作者：
MIETTINEN, PJ;BERGER, JE;DERYNCK, R
通讯作者：
DERYNCK, R
影响因子：
51.1
作者：
Mitsudomi, Tetsuya;Morita, Satoshi;Fukuoka, Masahiro
通讯作者：
Fukuoka, Masahiro
影响因子：
64.8
作者：
Morris, Erick J.;Ji, Jun-Yuan;Yang, Fajun;Di Stefano, Luisa;Herr, Anabel;Moon, Nam-Sung;Kwon, Eun-Jeong;Haigis, Kevin M.;Naar, Anders M.;Dyson, Nicholas J.
通讯作者：
Dyson, Nicholas J.
影响因子：
64.8
作者：
Garnett, Mathew J.;Edelman, Elena J.;Heidorn, Sonja J.;Greenman, Chris D.;Dastur, Anahita;Lau, King Wai;Greninger, Patricia;Thompson, I. Richard;Luo, Xi;Soares, Jorge;Liu, Qingsong;Iorio, Francesco;Surdez, Didier;Chen, Li;Milano, Randy J.;Bignell, Graham R.;Tam, Ah T.;Davies, Helen;Stevenson, Jesse A.;Barthorpe, Syd;Lutz, Stephen R.;Kogera, Fiona;Lawrence, Karl;McLaren-Douglas, Anne;Mitropoulos, Xeni;Mironenko, Tatiana;Thi, Helen;Richardson, Laura;Zhou, Wenjun;Jewitt, Frances;Zhang, Tinghu;O'Brien, Patrick;Boisvert, Jessica L.;Price, Stacey;Hur, Wooyoung;Yang, Wanjuan;Deng, Xianming;Butler, Adam;Choi, Hwan Geun;Chang, JaeWon;Baselga, Jose;Stamenkovic, Ivan;Engelman, Jeffrey A.;Sharma, Sreenath V.;Delattre, Olivier;Saez-Rodriguez, Julio;Gray, Nathanael S.;Settleman, Jeffrey;Futreal, P. Andrew;Haber, Daniel A.;Stratton, Michael R.;Ramaswamy, Sridhar;McDermott, Ultan;Benes, Cyril H.
通讯作者：
Benes, Cyril H.