title: Chimeric mouse tumor models reveal differences in pathway activation between ERBB family- and KRAS-dependent lung adenocarcinomas.
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 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.
authors.affiliation: [1] AVEO Pharmaceuticals, Cambridge, Massachusetts, USA. [2] These authors contributed equally to this work.
authors.forename: Yinghui
authors.initials: Y
authors.lastname: Zhou
authors.forename: William M
authors.initials: WM
authors.lastname: Rideout
authors.forename: Tong
authors.initials: T
authors.lastname: Zi
authors.forename: Angela
authors.initials: A
authors.lastname: Bressel
authors.forename: Shailaja
authors.initials: S
authors.lastname: Reddypalli
authors.forename: Rebecca
authors.initials: R
authors.lastname: Rancourt
authors.forename: Jin-Kyeung
authors.initials: JK
authors.lastname: Woo
authors.forename: James W
authors.initials: JW
authors.lastname: Horner
authors.forename: Lynda
authors.initials: L
authors.lastname: Chin
authors.forename: M Isabel
authors.initials: MI
authors.lastname: Chiu
authors.forename: Marcus
authors.initials: M
authors.lastname: Bosenberg
authors.forename: Tyler
authors.initials: T
authors.lastname: Jacks
authors.forename: Steven C
authors.initials: SC
authors.lastname: Clark
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Depinho
authors.forename: Murray O
authors.initials: MO
authors.lastname: Robinson
authors.forename: Joerg
authors.initials: J
authors.lastname: Heyer
mesh_terms: 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
chemical_list: D010879:Piperazines; D011799:Quinazolines; D066246:ErbB Receptors; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); C525087:MP 412