Spontaneous Genomic Alterations in a Chimeric Model of Colorectal Cancer Enable Metastasis and Guide Effective Combinatorial Therapy |
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| Authors: | Yinghui Zhou William M Rideout III Angela Bressel Sireesha Yalavarthi Tong Zi Darren Potz Samuel Farlow Joelle Brodeur Anthony Monti Shailaja Reddipalli Qiurong Xiao Steve Bottega Bin Feng M Isabel Chiu Marcus Bosenberg Joerg Heyer |
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| Institution: | 1. Department of Research, AVEO Pharmaceuticals, Inc., Cambridge, Massachusetts, United States of America.; 2. Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut, United States of America.; Cedars-Sinai Medical Center, United States of America, |
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| 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. |
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