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

• Published in: Cell Vol. 185; no. 11; pp. 1974 - 1985.e12
• Main Authors: Mo, Xiulei, Niu, Qiankun, Ivanov, Andrey A., Tsang, Yiu Huen, Tang, Cong, Shu, Changfa, Li, Qianjin, Qian, Kun, Wahafu, Alafate, Doyle, Sean P., Cicka, Danielle, Yang, Xuan, Fan, Dacheng, Reyna, Matthew A., Cooper, Lee A.D., Moreno, Carlos S., Zhou, Wei, Owonikoko, Taofeek K., Lonial, Sagar, Khuri, Fadlo R., Du, Yuhong, Ramalingam, Suresh S., Mills, Gordon B., Fu, Haian
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26.05.2022
• Subjects: biosensors; BRETn; cancer genomics; cancer target; Carcinogenesis; driver mutations; genomics; Humans; interactome; Kelch-Like ECH-Associated Protein 1 - genetics; Kelch-Like ECH-Associated Protein 1 - metabolism; landscapes; mutants; Mutation; neoplasms; Neoplasms - genetics; neoPPI; NF-E2-Related Factor 2 - metabolism; oncogene; patients; precision medicine; protein-protein interaction; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins B-raf - metabolism; systems biology; tumor suppressor; driver mutations; systems biology; cancer target; BRETn; neoPPI; cancer genomics; tumor suppressor; protein-protein interaction; interactome; oncogene; BRET(n)
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2022.04.014

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. [Display omitted] •qHT-dS platform enables differential PPI mapping at single residue resolution•Pan cancer analysis uncovers widespread driver-mutation-directed neoPPIs•BRAFV600E/KEAP1 neoPPI-rewired NRF2-pathway confers therapeutic vulnerability•Annotated neoPPI dataset serves as resource to advance variant-specific target discovery Pan cancer analysis unveils widespread driver-mutation-directed protein-protein interactions, informing variant-mediated rewiring of oncogenic programs and therapeutic approaches for precision medicine.