Chimeric mouse tumor models reveal differences in pathway activation between ERBB family- and KRAS-dependent lung adenocarcinomas

被引：55

作者：

Zhou, Yinghui ^{[1
]}

Rideout, William M., III ^{[1
]}

Zi, Tong ^{[1
]}

Bressel, Angela ^{[1
]}

Reddypalli, Shailaja ^{[1
]}

Rancourt, Rebecca ^{[1
]}

Woo, Jin-Kyeung ^{[1
]}

Horner, James W. ^{[3
,4
,5
]}

Chin, Lynda ^{[2
]}

Chiu, M. Isabel ^{[1
]}

Bosenberg, Marcus ^{[6
]}

Jacks, Tyler ^{[7
,8
,9
]}

Clark, Steven C. ^{[1
]}

DePinho, Ronald A. ^{[3
,4
,5
]}

Robinson, Murray O. ^{[1
]}

Heyer, Joerg ^{[1
]}

机构：

[1] AVEO Pharmaceut, Cambridge, MA USA

[2] Harvard Univ, Sch Med, Dana Farber Canc Inst,Dept Med Oncol, Belfer Inst Appl Canc Sci,Dept Dermatol, Boston, MA 02115 USA

[3] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med, Boston, MA 02115 USA

[4] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Genet, Boston, MA 02115 USA

[5] Harvard Univ, Sch Med, Dept Med & Genet, Boston, MA 02115 USA

[6] Yale Univ, Sch Med, Dept Dermatol, New Haven, CT 06510 USA

[7] MIT, Koch Inst, Cambridge, MA 02139 USA

[8] MIT, Dept Biol, Cambridge, MA 02139 USA

[9] MIT, Howard Hughes Med Inst, Cambridge, MA 02139 USA

来源：

NATURE BIOTECHNOLOGY | 2010年 / 28卷 / 01期

关键词：

GROWTH-FACTOR-RECEPTOR; TYROSINE KINASE INHIBITOR; GENE-EXPRESSION; MAMMARY EPITHELIUM; CANCER; RESISTANCE; MUTATION; GEFITINIB; EGFR; ERLOTINIB;

D O I：

10.1038/nbt.1595

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

To recapitulate the stochastic nature of human cancer development, we have devised a strategy for generating mouse tumor models that involves stepwise genetic manipulation of embryonic stem (ES) cells and chimera generation. Tumors in the chimeric animals develop from engineered cells in the context of normal tissue. Adenocarcinomas arising in an allelic series of lung cancer models containing HER2 (also known as ERBB2), KRAS or EGFR oncogenes exhibit features of advanced malignancies. Treatment of EGFR(L858R) and KRAS(G12V) chimeric models with an EGFR inhibitor resulted in near complete tumor regression and no response to the treatment, respectively, accurately reflecting previous clinical observations. Transcriptome and immunohistochemical analyses reveal that PI3K pathway activation is unique to ERBB family tumors whereas KRAS-driven tumors show activation of the JNK/SAP pathway, suggesting points of therapeutic intervention for this difficult-to-treat tumor category.

引用

页码：71 / U102

页数：9

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