Chimeric mouse tumor models reveal differences in pathway activation between ERBB family- and KRAS-dependent lung adenocarcinomas.
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.
Zhou
Yinghui
Y
[1] AVEO Pharmaceuticals, Cambridge, Massachusetts, USA. [2] These authors contributed equally to this work.
Rideout
William M
WM
Zi
Tong
T
Bressel
Angela
A
Reddypalli
Shailaja
S
Rancourt
Rebecca
R
Woo
Jin-Kyeung
JK
Horner
James W
JW
Chin
Lynda
L
Chiu
M Isabel
MI
Bosenberg
Marcus
M
Jacks
Tyler
T
Clark
Steven C
SC
Depinho
Ronald A
RA
Robinson
Murray O
MO
Heyer
Joerg
J
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002678:Chimera / Q000378:metabolism*; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells / Q000187:drug effects / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D010879:Piperazines / Q000494:pharmacology; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology; D012131:Respiratory Insufficiency / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects
D010879:Piperazines; D011799:Quinazolines; D066246:ErbB Receptors; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); C525087:MP 412