RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer

被引：617

作者：

Niederst, Matthew J. ^{[1
,2
]}

Sequist, Lecia V. ^{[1
,2
]}

Poirier, John T. ^{[3
]}

Mermel, Craig H. ^{[4
,5
]}

Lockerman, Elizabeth L. ^{[1
,2
]}

Garcia, Angel R. ^{[1
,2
]}

Katayama, Ryohei ^{[1
,2
]}

Costa, Carlotta ^{[1
,2
]}

Ross, Kenneth N. ^{[1
,2
]}

Moran, Teresa ^{[1
,2
]}

Howe, Emily ^{[1
,2
]}

Fulton, Linnea E. ^{[1
,2
]}

Mulvey, Hillary E. ^{[1
,2
]}

Bernardo, Lindsay A. ^{[5
,6
]}

Mohamoud, Farhiya ^{[1
,2
]}

Miyoshi, Norikatsu ^{[2
,7
]}

VanderLaan, Paul A. ^{[8
]}

Costa, Daniel B. ^{[9
]}

Jaenne, Pasi A. ^{[10
,11
,12
]}

Borger, Darrell R. ^{[1
,2
]}

Ramaswamy, Sridhar ^{[1
,2
,4
]}

Shioda, Toshi ^{[2
,7
]}

Iafrate, Anthony J. ^{[5
,6
]}

Getz, Gad ^{[2
,4
]}

Rudin, Charles M. ^{[3
]}

Mino-Kenudson, Mari ^{[5
,6
]}

Engelman, Jeffrey A. ^{[1
,2
]}

机构：

[1] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA

[2] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA

[3] Mem Sloan Kettering Canc Ctr, Thorac Oncol Serv, New York, NY 10065 USA

[4] Broad Inst MIT & Harvard, Canc Genome Comparat Anal Grp, Cambridge, MA 02142 USA

[5] Massachusetts Gen Hosp, Ctr Canc, Dept Pathol, Boston, MA 02114 USA

[6] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA

[7] Massachusetts Gen Hosp, Ctr Canc, Mol Profiling Lab, Boston, MA 02114 USA

[8] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Pathol, Boston, MA 02115 USA

[9] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Med,Div Hematol Oncol, Boston, MA 02115 USA

[10] Dana Farber Canc Inst, Belfer Inst Appl Sci, Dept Med Oncol, Boston, MA 02215 USA

[11] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA

[12] Harvard Univ, Sch Med, Boston, MA 02115 USA

来源：

NATURE COMMUNICATIONS | 2015年 / 6卷

关键词：

FACTOR RECEPTOR MUTATIONS; ACQUIRED-RESISTANCE; GEFITINIB; AMPLIFICATION; CHEMOTHERAPY; INHIBITORS; GENE;

D O I：

10.1038/ncomms7377

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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.

引用

页数：10

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