A personalized platform identifies trametinib plus zoledronate for a patient with KRAS-mutant metastatic colorectal cancer

Colorectal cancer remains a leading source of cancer mortality worldwide. Initial response is often followed by emergent resistance that is poorly responsive to targeted therapies, reflecting currently undruggable cancer drivers such as and overall genomic complexity. Here, we report a novel approac...

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Published in:Science advances 2019-05, Vol.5 (5), p.eaav6528-eaav6528
Main Authors: Bangi, Erdem, Ang, Celina, Smibert, Peter, Uzilov, Andrew V, Teague, Alexander G, Antipin, Yevgeniy, Chen, Rong, Hecht, Chana, Gruszczynski, Nelson, Yon, Wesley J, Malyshev, Denis, Laspina, Denise, Selkridge, Isaiah, Rainey, Hope, Moe, Aye S, Lau, Chun Yee, Taik, Patricia, Wilck, Eric, Bhardwaj, Aarti, Sung, Max, Kim, Sara, Yum, Kendra, Sebra, Robert, Donovan, Michael, Misiukiewicz, Krzysztof, Schadt, Eric E, Posner, Marshall R, Cagan, Ross L
Format: Article
Language:English
Subjects:
Cancer
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Summary:Colorectal cancer remains a leading source of cancer mortality worldwide. Initial response is often followed by emergent resistance that is poorly responsive to targeted therapies, reflecting currently undruggable cancer drivers such as and overall genomic complexity. Here, we report a novel approach to developing a personalized therapy for a patient with treatment-resistant metastatic KRAS-mutant colorectal cancer. An extensive genomic analysis of the tumor's genomic landscape identified nine key drivers. A transgenic model that altered orthologs of these nine genes in the hindgut was developed; a robotics-based screen using this platform identified trametinib plus zoledronate as a candidate treatment combination. Treating the patient led to a significant response: Target and nontarget lesions displayed a strong partial response and remained stable for 11 months. By addressing a disease's genomic complexity, this personalized approach may provide an alternative treatment option for recalcitrant disease such as KRAS-mutant colorectal cancer.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.aav6528