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

Bangi, E. et al. (2019) A personalized platform identifies trametinib plus zoledronate for a patient with KRAS-mutant metastatic colorectal cancer. Science Advances, 5(5), eaav6528. (doi: 10.1126/sciadv.aav6528) (PMID:31131321) (PMCID:PMC6531007)

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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.

Item Type:Articles
Additional Information:Funding: This work was supported by funds from the Dean’s Office and by U54OD020353 from the NIH.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Cagan, Professor Ross
Authors: Bangi, E., Ang, C., Smibert, P., Uzilov, A. V., Teague, A. G., Antipin, Y., Chen, R., Hecht, C., Gruszczynski, N., Yon, W. J., Malyshev, D., Laspina, D., Selkridge, I., Rainey, H., Moe, A. S., Lau, C. Y., Taik, P., Wilck, E., Bhardwaj, A., Sung, M., Kim, S., Yum, K., Sebra, R., Donovan, M., Misiukiewicz, K., Schadt, E. E., Posner, M. R., and Cagan, R. L.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Science Advances
Publisher:American Association for the Advancement of Science
ISSN:2375-2548
ISSN (Online):2375-2548
Copyright Holders:Copyright © 2019 The Authors, some rights reserved
First Published:First published in Science Advances 5(5):eaav6528
Publisher Policy:Reproduced under a Creative Commons licence

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