April 21, 2020  |  

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

Authors: Bangi, Erdem and Ang, Celina and Smibert, Peter and Uzilov, Andrew V and Teague, Alexander G and Antipin, Yevgeniy and Chen, Rong and Hecht, Chana and Gruszczynski, Nelson and Yon, Wesley J and Malyshev, Denis and Laspina, Denise and Selkridge, Isaiah and Rainey, Hope and Moe, Aye S and Lau, Chun Yee and Taik, Patricia and Wilck, Eric and Bhardwaj, Aarti and Sung, Max and Kim, Sara and Yum, Kendra and Sebra, Robert and Donovan, Michael and Misiukiewicz, Krzysztof and Schadt, Eric E and Posner, Marshall R and Cagan, Ross L

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 KRAS 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 Drosophila 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.

Journal: Science advances
DOI: 10.1126/sciadv.aav6528
Year: 2019

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