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

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.

• Authors: Xiulei Mo, Qiankun Niu, Andrey A Ivanov, Yiu Huen Tsang, Cong Tang, Changfa Shu, Qianjin Li, Kun Qian, Alafate Wahafu, Sean P Doyle, Danielle Cicka, Xuan Yang, Dacheng Fan, Matthew A Reyna, Lee A D Cooper, Carlos S Moreno, Wei Zhou, Taofeek K Owonikoko, Sagar Lonial, Fadlo R Khuri, Yuhong Du, Suresh S Ramalingam, Gordon B Mills, Haian Fu
• Journal: Cell (Cell) Vol. 185 Issue 11 Pg. 1974-1985.e12 (05 26 2022) ISSN: 1097-4172 [Electronic] United States
• PMID: 35512704 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2022 Elsevier Inc. All rights reserved.

Chemical References

• Kelch-Like ECH-Associated Protein 1
• NF-E2-Related Factor 2
• Proto-Oncogene Proteins B-raf

Topics

• Carcinogenesis
• Humans
• Kelch-Like ECH-Associated Protein 1 (genetics, metabolism)
• Mutation
• NF-E2-Related Factor 2 (metabolism)
• Neoplasms (genetics)
• Proto-Oncogene Proteins B-raf (genetics, metabolism)