title: Spontaneous genomic alterations in a chimeric model of colorectal cancer enable metastasis and guide effective combinatorial therapy.
abstract: Colon cancer is the second most common cause of cancer mortality in the Western world with metastasis commonly present at the time of diagnosis. Screening for propagation and metastatic behavior in a novel chimeric-mouse colon cancer model, driven by mutant p53 and β-Catenin, led to the identification of a unique, invasive adenocarcinoma. Comparison of the genome of this tumor, CB42, with genomes from non-propagating tumors by array CGH and sequencing revealed an amplicon on chromosome five containing CDK6 and CDK14, and a KRAS mutation, respectively. Single agent small molecule inhibition of either CDK6 or MEK, a kinase downstream of KRAS, led to tumor growth inhibition in vivo whereas combination therapy not only led to regression of the subcutaneous tumors, but also near complete inhibition of lung metastasis; thus, genomic analysis of this tumor led to effective, individualized treatment.
authors.affiliation: Department of Research, AVEO Pharmaceuticals, Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Yinghui
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Research, AVEO Pharmaceuticals, Inc., Cambridge, Massachusetts, United States of America.
authors.forename: William M
authors.initials: WM
authors.lastname: Rideout
authors.affiliation: Department of Research, AVEO Pharmaceuticals, Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Angela
authors.initials: A
authors.lastname: Bressel
authors.affiliation: Department of Research, AVEO Pharmaceuticals, Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Sireesha
authors.initials: S
authors.lastname: Yalavarthi
authors.affiliation: Department of Research, AVEO Pharmaceuticals, Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Tong
authors.initials: T
authors.lastname: Zi
authors.affiliation: Department of Research, AVEO Pharmaceuticals, Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Darren
authors.initials: D
authors.lastname: Potz
authors.affiliation: Department of Research, AVEO Pharmaceuticals, Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Samuel
authors.initials: S
authors.lastname: Farlow
authors.affiliation: Department of Research, AVEO Pharmaceuticals, Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Joelle
authors.initials: J
authors.lastname: Brodeur
authors.affiliation: Department of Research, AVEO Pharmaceuticals, Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Anthony
authors.initials: A
authors.lastname: Monti
authors.affiliation: Department of Research, AVEO Pharmaceuticals, Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Shailaja
authors.initials: S
authors.lastname: Reddipalli
authors.affiliation: Department of Research, AVEO Pharmaceuticals, Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Qiurong
authors.initials: Q
authors.lastname: Xiao
authors.affiliation: Department of Research, AVEO Pharmaceuticals, Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Steve
authors.initials: S
authors.lastname: Bottega
authors.affiliation: Department of Research, AVEO Pharmaceuticals, Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Bin
authors.initials: B
authors.lastname: Feng
authors.affiliation: Department of Research, AVEO Pharmaceuticals, Inc., Cambridge, Massachusetts, United States of America.
authors.forename: M Isabel
authors.initials: MI
authors.lastname: Chiu
authors.affiliation: Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Marcus
authors.initials: M
authors.lastname: Bosenberg
authors.affiliation: Department of Research, AVEO Pharmaceuticals, Inc., Cambridge, Massachusetts, United States of America.
authors.forename: Joerg
authors.initials: J
authors.lastname: Heyer
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D000818:Animals; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000556:secondary; D051379:Mice; D009154:Mutation; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000628:therapy
chemical_list: D009363:Neoplasm Proteins