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Cancer Discov. 2015 Feb;5(2):154-67. doi: 10.1158/2159-8290.CD-14-0552. Epub 2014 Dec 12.

Linking tumor mutations to drug responses via a quantitative chemical-genetic interaction map.

Author information

1
University of California, San Francisco, San Francisco, California.
2
Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts.
3
Center for the Science of Therapeutics, Broad Institute, Cambridge, Massachusetts. Howard Hughes Medical Institute, Bethesda, Maryland.
4
University of California, San Francisco, San Francisco, California. Howard Hughes Medical Institute, Bethesda, Maryland.
5
University of California, San Francisco, San Francisco, California. bandyopadhyays@cc.ucsf.edu andrei.goga@ucsf.edu.

Abstract

There is an urgent need in oncology to link molecular aberrations in tumors with therapeutics that can be administered in a personalized fashion. One approach identifies synthetic-lethal genetic interactions or dependencies that cancer cells acquire in the presence of specific mutations. Using engineered isogenic cells, we generated a systematic and quantitative chemical-genetic interaction map that charts the influence of 51 aberrant cancer genes on 90 drug responses. The dataset strongly predicts drug responses found in cancer cell line collections, indicating that isogenic cells can model complex cellular contexts. Applying this dataset to triple-negative breast cancer, we report clinically actionable interactions with the MYC oncogene, including resistance to AKT-PI3K pathway inhibitors and an unexpected sensitivity to dasatinib through LYN inhibition in a synthetic lethal manner, providing new drug and biomarker pairs for clinical investigation. This scalable approach enables the prediction of drug responses from patient data and can accelerate the development of new genotype-directed therapies.

SIGNIFICANCE:

Determining how the plethora of genomic abnormalities that exist within a given tumor cell affects drug responses remains a major challenge in oncology. Here, we develop a new mapping approach to connect cancer genotypes to drug responses using engineered isogenic cell lines and demonstrate how the resulting dataset can guide clinical interrogation.

PMID:
25501949
PMCID:
PMC4407699
DOI:
10.1158/2159-8290.CD-14-0552
[Indexed for MEDLINE]
Free PMC Article
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