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

Maria M. Martins, Alicia Y. Zhou, Alexandra Corella, Dai Horiuchi, Christina Yau, Taha Rakshandehroo, John D. Gordan, Rebecca S. Levin, Jeff Johnson, John Jascur, Mike Shales, Antonio Sorrentino, Jaime Cheah, Paul A. Clemons, Alykhan F. Shamji, Stuart L. Schreiber, Nevan J. Krogan, Kevan M. Shokat, Frank McCormick, Andrei GogaSourav Bandyopadhyay*

*Corresponding author for this work

Research output: Contribution to journalArticle

30 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)154-167
Number of pages14
JournalCancer discovery
Volume5
Issue number2
DOIs
StatePublished - Jan 1 2015

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ASJC Scopus subject areas

  • Oncology

Cite this

Martins, M. M., Zhou, A. Y., Corella, A., Horiuchi, D., Yau, C., Rakshandehroo, T., Gordan, J. D., Levin, R. S., Johnson, J., Jascur, J., Shales, M., Sorrentino, A., Cheah, J., Clemons, P. A., Shamji, A. F., Schreiber, S. L., Krogan, N. J., Shokat, K. M., McCormick, F., ... Bandyopadhyay, S. (2015). Linking tumor mutations to drug responses via a quantitative chemical–genetic interaction map. Cancer discovery, 5(2), 154-167. https://doi.org/10.1158/2159-8290.CD-14-0552