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. Khuri; Yuhong Du; Suresh S. Ramalingam; Gordon B. Mills; Haian Fu

doi:10.1016/j.cell.2022.04.014

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

Cell Developmental and Cancer Biology

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

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 BRAF^V600E/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 language	English (US)
Pages (from-to)	1974-1985.e12
Journal	Cell
Volume	185
Issue number	11
DOIs	https://doi.org/10.1016/j.cell.2022.04.014
State	Published - 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

General Biochemistry, Genetics and Molecular Biology

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Mo, X., Niu, Q., Ivanov, A. A., Tsang, Y. H., Tang, C., Shu, C., Li, Q., Qian, K., Wahafu, A., Doyle, S. P., Cicka, D., Yang, X., Fan, D., Reyna, M. A., Cooper, L. A. D., Moreno, C. S., Zhou, W., Owonikoko, T. K., Lonial, S., ... Fu, H. (2022). Systematic discovery of mutation-directed neo-protein-protein interactions in cancer. Cell, 185(11), 1974-1985.e12. https://doi.org/10.1016/j.cell.2022.04.014

Mo, X, Niu, Q, Ivanov, AA, Tsang, YH, Tang, C, Shu, C, Li, Q, Qian, K, Wahafu, A, Doyle, SP, Cicka, D, Yang, X, Fan, D, Reyna, MA, Cooper, LAD, Moreno, CS, Zhou, W, Owonikoko, TK, Lonial, S, Khuri, FR, Du, Y, Ramalingam, SS, Mills, GB & Fu, H 2022, 'Systematic discovery of mutation-directed neo-protein-protein interactions in cancer', Cell, vol. 185, no. 11, pp. 1974-1985.e12. https://doi.org/10.1016/j.cell.2022.04.014

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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.",

keywords = "BRET, cancer genomics, cancer target, driver mutations, interactome, neoPPI, oncogene, protein-protein interaction, systems biology, tumor suppressor",

author = "Xiulei Mo and Qiankun Niu and Ivanov, {Andrey A.} and Tsang, {Yiu Huen} and Cong Tang and Changfa Shu and Qianjin Li and Kun Qian and Alafate Wahafu and Doyle, {Sean P.} and Danielle Cicka and Xuan Yang and Dacheng Fan and Reyna, {Matthew A.} and Cooper, {Lee A.D.} and Moreno, {Carlos S.} and Wei Zhou and Owonikoko, {Taofeek K.} and Sagar Lonial and Khuri, {Fadlo R.} and Yuhong Du and Ramalingam, {Suresh S.} and Mills, {Gordon B.} and Haian Fu",

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doi = "10.1016/j.cell.2022.04.014",

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AU - Mo, Xiulei

AU - Niu, Qiankun

AU - Ivanov, Andrey A.

AU - Tsang, Yiu Huen

AU - Tang, Cong

AU - Shu, Changfa

AU - Li, Qianjin

AU - Qian, Kun

AU - Wahafu, Alafate

AU - Doyle, Sean P.

AU - Cicka, Danielle

AU - Yang, Xuan

AU - Fan, Dacheng

AU - Reyna, Matthew A.

AU - Cooper, Lee A.D.

AU - Moreno, Carlos S.

AU - Zhou, Wei

AU - Owonikoko, Taofeek K.

AU - Lonial, Sagar

AU - Khuri, Fadlo R.

AU - Du, Yuhong

AU - Ramalingam, Suresh S.

AU - Mills, Gordon B.

AU - Fu, Haian

PY - 2022/5/26

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N2 - 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.

AB - 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.

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KW - cancer genomics

KW - cancer target

KW - driver mutations

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KW - protein-protein interaction

KW - systems biology

KW - tumor suppressor

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SP - 1974-1985.e12

JO - Cell

JF - Cell

IS - 11

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

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