Abstract
Comprehensive sequencing of patient tumors reveals genomic mutations across tumor types that enable tumorigenesis and progression. A subset of oncogenic driver mutations results in neomorphic activity where the mutant protein mediates functions not engaged by the parental molecule. Here, we identify prevalent variant-enabled neomorph-protein-protein interactions (neoPPI) with a quantitative high-throughput differential screening (qHT-dS) platform. The coupling of highly sensitive BRET biosensors with miniaturized coexpression in an ultra-HTS format allows large-scale monitoring of the interactions of wild-type and mutant variant counterparts with a library of cancer-associated proteins in live cells. The screening of 17,792 interactions with 2,172,864 data points revealed a landscape of gain of interactions encompassing both oncogenic and tumor suppressor mutations. For example, the recurrent BRAF V600E lesion mediates KEAP1 neoPPI, rewiring a BRAFV600E/KEAP1 signaling axis and creating collateral vulnerability to NQO1 substrates, offering a combination therapeutic strategy. Thus, cancer genomic alterations can create neo-interactions, informing variant-directed therapeutic approaches for precision medicine.
Original language | English (US) |
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Pages (from-to) | 1974-1985.e12 |
Journal | Cell |
Volume | 185 |
Issue number | 11 |
DOIs | |
State | Published - May 26 2022 |
Keywords
- BRET
- cancer genomics
- cancer target
- driver mutations
- interactome
- neoPPI
- oncogene
- protein-protein interaction
- systems biology
- tumor suppressor
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology