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

Y Zhou, WM Rideout, T Zi, A Bressel… - Nature …, 2010 - nature.com
Y Zhou, WM Rideout, T Zi, A Bressel, S Reddypalli, R Rancourt, JK Woo, JW Horner, L Chin…
Nature biotechnology, 2010nature.com
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 …
Abstract
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 EGFRL858R and KRASG12V 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.
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