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

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

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

Abstract

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.

Original languageEnglish
Article numberaav6528
JournalScience advances
Volume5
Issue number5
DOIs
StatePublished - 2019

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