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

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. KhuriYuhong Du, Suresh S. Ramalingam, Gordon B. Mills, Haian Fu

Research output: Contribution to journalArticlepeer-review

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 languageEnglish (US)
Pages (from-to)1974-1985.e12
JournalCell
Volume185
Issue number11
DOIs
StatePublished - 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

  • Biochemistry, Genetics and Molecular Biology(all)

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