Synthetic Lethality Aids Precision Cancer Therapy

SCHEMATIC employs a combinatorial CRISPR library to simultaneously disrupt pairs of genes implicated in cancer-relevant pathways, screening them across diverse tumour cell lines. These high-throughput screenings identified 266 synthetic lethal interactions with high penetrance, meaning they robustly appeared across multiple tumour types.

These interactions were cross-referenced with drug sensitivity data, revealing actionable mutation-drug pairings. For instance, CHEK1-mutated cancer cells were shown to be sensitive to AKT1 inhibition, a finding validated by multiple AKT inhibitors. Another key discovery was the vulnerability of KDM5C- or KDM6A-mutated tumours to PARP7 inhibition.

The study highlights the potential of synthetic lethality to identify tumour-specific vulnerabilities and paves the way for personalised therapies. The high rate of cross-tumour penetrance among the interactions suggests a broader applicability of these findings than previously assumed. Nonetheless, limitations in the breadth of tumour contexts screened suggest the need for expansion to cover a greater variety of genetic and tumour backgrounds.

The research, led by Samson Fong and Trey Ideker at University of California San Diego, was published in Nature Genetics last week.