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 |
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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 > School 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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