A multilineage screen identifies actionable synthetic lethal interactions in human cancers

Samson H Fong; Brent M Kuenzi; Nicole M Mattson; John Lee; Kyle Sanchez; Ana Bojorquez-Gomez; Kyle Ford; Brenton P Munson; Katherine Licon; Sarah Bergendahl; John Paul Shen; Jason F Kreisberg; Prashant Mali; Jeffrey H Hager; Michael A White; Trey Ideker

doi:10.1038/s41588-024-01971-9

A multilineage screen identifies actionable synthetic lethal interactions in human cancers

Nat Genet. 2024 Nov 18. doi: 10.1038/s41588-024-01971-9. Online ahead of print.

Authors

Samson H Fong^{1

2}, Brent M Kuenzi¹, Nicole M Mattson¹, John Lee¹, Kyle Sanchez¹, Ana Bojorquez-Gomez¹, Kyle Ford², Brenton P Munson^{1

2}, Katherine Licon¹, Sarah Bergendahl¹, John Paul Shen¹, Jason F Kreisberg¹, Prashant Mali², Jeffrey H Hager³, Michael A White³, Trey Ideker^{4

5

6}

Affiliations

¹ Division of Human Genomics and Precision Medicine, Department of Medicine, University of California San Diego, La Jolla, CA, USA.
² Department of Bioengineering, University of California San Diego, La Jolla, CA, USA.
³ IDEAYA Biosciences, San Francisco, CA, USA.
⁴ Division of Human Genomics and Precision Medicine, Department of Medicine, University of California San Diego, La Jolla, CA, USA. [email protected].
⁵ Department of Bioengineering, University of California San Diego, La Jolla, CA, USA. [email protected].
⁶ Department of Computer Science and Engineering, University of California San Diego, La Jolla, CA, USA. [email protected].

PMID: 39558023
DOI: 10.1038/s41588-024-01971-9

Abstract

Cancers are driven by alterations in diverse genes, creating dependencies that can be therapeutically targeted. However, many genetic dependencies have proven inconsistent across tumors. Here we describe SCHEMATIC, a strategy to identify a core network of highly penetrant, actionable genetic interactions. First, fundamental cellular processes are perturbed by systematic combinatorial knockouts across tumor lineages, identifying 1,805 synthetic lethal interactions (95% unreported). Interactions are then analyzed by hierarchical pooling, revealing that half segregate reliably by tissue type or biomarker status (51%) and a substantial minority are penetrant across lineages (34%). Interactions converge on 49 multigene systems, including MAPK signaling and BAF transcriptional regulatory complexes, which become essential on disruption of polymerases. Some 266 interactions translate to robust biomarkers of drug sensitivity, including frequent genetic alterations in the KDM5C/6A histone demethylases, which sensitize to inhibition of TIPARP (PARP7). SCHEMATIC offers a context-aware, data-driven approach to match genetic alterations to targeted therapies.

Abstract

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