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

Authors :
Xuan Yang
Gordon B Mill
Lee Cooper
Yiu Huen Tsang
Andrey A. Ivanov
Dacheng Fan
Matthew A. Reyna
Wei Zhou
Xiulei Mo
Suresh S. Ramalingam
Yuhong Du
Sagar Lonial
Cong Tang
Carlos S. Moreno
Alafate Wahafu
Haian Fu
Changfa Shu
Danielle Cicka
Taofeek K. Owonikoko
Fadlo R. Khuri
Sean P. Doyle
Qiankun Niu
Publication Year :
2021
Publisher :
Cold Spring Harbor Laboratory, 2021.

Abstract

SUMMARYComprehensive 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.

Details

Database :
OpenAIRE
Accession number :
edsair.doi...........5694f117ed2815a235d4cafaec84f878