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Integration of multiple biological contexts reveals principles of synthetic lethality that affect reproducibility

Author

Listed:
  • Angel A. Ku

    (University of California, San Francisco)

  • Hsien-Ming Hu

    (University of California, San Francisco)

  • Xin Zhao

    (University of California, San Francisco)

  • Khyati N. Shah

    (University of California, San Francisco)

  • Sameera Kongara

    (University of California, San Francisco)

  • Di Wu

    (University of California, San Francisco)

  • Frank McCormick

    (University of California, San Francisco)

  • Allan Balmain

    (University of California, San Francisco)

  • Sourav Bandyopadhyay

    (University of California, San Francisco
    University of California, San Francisco)

Abstract

Synthetic lethal screens have the potential to identify new vulnerabilities incurred by specific cancer mutations but have been hindered by lack of agreement between studies. In the case of KRAS, we identify that published synthetic lethal screen hits significantly overlap at the pathway rather than gene level. Analysis of pathways encoded as protein networks could identify synthetic lethal candidates that are more reproducible than those previously reported. Lack of overlap likely stems from biological rather than technical limitations as most synthetic lethal phenotypes are strongly modulated by changes in cellular conditions or genetic context, the latter determined using a pairwise genetic interaction map that identifies numerous interactions that suppress synthetic lethal effects. Accounting for pathway, cellular and genetic context nominates a DNA repair dependency in KRAS-mutant cells, mediated by a network containing BRCA1. We provide evidence for why most reported synthetic lethals are not reproducible which is addressable using a multi-faceted testing framework.

Suggested Citation

  • Angel A. Ku & Hsien-Ming Hu & Xin Zhao & Khyati N. Shah & Sameera Kongara & Di Wu & Frank McCormick & Allan Balmain & Sourav Bandyopadhyay, 2020. "Integration of multiple biological contexts reveals principles of synthetic lethality that affect reproducibility," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16078-y
    DOI: 10.1038/s41467-020-16078-y
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