Systematic discovery of mutation-directed neo-protein-protein interactions in cancer

Mo, X.; Niu, Q.; Ivanov, A. A.; Tsang, Y. H.; Tang, C.; Shu, C.; Wahafu, A.; Doyle, S.; Cicka, D.; Yang, X.; Fan, D.; Reyna, M. A.; Cooper, L. A. D.; Moreno, C. S.; Zhou, W.; Owonikoko, T.; Lonial, S.; Khuri, F. R.; Du, Y.; Ramalingam, S. S.; Mill, G. B.; Fu, H.

doi:10.1101/2021.10.03.462422

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bioRxiv · 10.1101/2021.10.03.462422

Systematic discovery of mutation-directed neo-protein-protein interactions in cancer

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Abstract

Comprehensive sequencing of patient tumors reveals numerous 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. Coupling of highly sensitive BRET biosensors with miniaturized co-expression in an ultra-HTS format allows large-scale monitoring of interactions of wild-type and mutant variant counterparts with a library of cancer-associated proteins in live cells. Screening of 13,392 interactions with 1,474,560 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.

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Mo, X., Niu, Q., Ivanov, A. A., Tsang, Y. H., Tang, C., Shu, C., Wahafu, A., Doyle, S., Cicka, D., Yang, X., Fan, D., Reyna, M. A., Cooper, L. A. D., Moreno, C. S., Zhou, W., Owonikoko, T., Lonial, S., Khuri, F. R., Du, Y., Ramalingam, S. S., Mill, G. B., Fu, H.. 2021-10-03. Systematic discovery of mutation-directed neo-protein-protein interactions in cancer. https://doi.org/10.1101/2021.10.03.462422

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