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

Sci Adv. 2019 May 22;5(5):eaav6528. doi: 10.1126/sciadv.aav6528.

Erdem Bangi ¹, Celina Ang ² ³, Peter Smibert ¹, Andrew V Uzilov ⁴ ⁵, Alexander G Teague ¹, Yevgeniy Antipin ⁴ ⁵, Rong Chen ⁴ ⁵, Chana Hecht ¹, Nelson Gruszczynski ¹, Wesley J Yon ¹, Denis Malyshev ¹, Denise Laspina ¹, Isaiah Selkridge ², Hope Rainey ², Aye S Moe ⁴ ⁵, Chun Yee Lau ⁴ ⁵, Patricia Taik ⁴ ⁵, Eric Wilck ⁶, Aarti Bhardwaj ², Max Sung ² ³, Sara Kim ⁷, Kendra Yum ⁷, Robert Sebra ⁴ ⁵, Michael Donovan ³ ⁸, Krzysztof Misiukiewicz ² ³, Eric E Schadt ⁴ ⁵ ³, Marshall R Posner ² ³, Ross L Cagan ¹ ³

Affiliations

1 Department of Cell, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
2 Division of Hematology and Medical Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
3 Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
4 Department of Genetics and Genomic Sciences and Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
5 SEMA4, a Mount Sinai Venture, 333 Ludlow Street, South Tower, 3rd floor, Stamford, CT 06902, USA.
6 Department of Radiology, The Mount Sinai Hospital, New York, NY 10029, USA.
7 Department of Pharmacy, The Mount Sinai Hospital, New York, NY 10029, USA.
8 Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

PMID: 31131321 DOI: 10.1126/sciadv.aav6528

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.

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Drug Repurposing Series

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