@article{5ed643325827403f9d9886fdde51164d,
title = "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.",
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",
note = "Funding Information: This work was supported by NCI {\textquoteright}s Cancer Target Discovery and Development ( CTD 2 ) Network ( U01CA217875 to H.F.; U01CA217842 to G.B.M.). The data were deposited to the NCI - CTD 2 Data Portal ( https://ocg.cancer.gov/programs/ctd2/data-portal ). This research was also supported in part by the NCI Emory Lung Cancer SPORE (S.R., H.F.; P50CA217691 ), Career Enhancement Program (X.M. and A.A.I., P50CA217691 ), Winship Cancer Institute ( NIH 5P30CA138292 ), and Winship Cancer Institute # IRG-17-181-06 from the American Cancer Society (A.A.I.). Emory initiative on Biological Discovery through Chemical Innovation (A.A.I.), the Imagine, Innovate and Impact (I3) Funds from the Emory School of Medicine and through the Georgia CTSA NIH award ( UL1-TR002378 ), and a kind gift from the Miriam and Sheldon Adelson Medical Research Foundation to G.B.M . Funding Information: This work was supported by NCI's Cancer Target Discovery and Development (CTD2) Network (U01CA217875 to H.F.; U01CA217842 to G.B.M.). The data were deposited to the NCI-CTD2 Data Portal (https://ocg.cancer.gov/programs/ctd2/data-portal). This research was also supported in part by the NCI Emory Lung Cancer SPORE (S.R. H.F.; P50CA217691), Career Enhancement Program (X.M. and A.A.I. P50CA217691), Winship Cancer Institute (NIH 5P30CA138292), and Winship Cancer Institute #IRG-17-181-06 from the American Cancer Society (A.A.I.). Emory initiative on Biological Discovery through Chemical Innovation (A.A.I.), the Imagine, Innovate and Impact (I3) Funds from the Emory School of Medicine and through the Georgia CTSA NIH award (UL1-TR002378), and a kind gift from the Miriam and Sheldon Adelson Medical Research Foundation to G.B.M. X.M. Q.N. A.A.I. Y.T.H. C.T. X.Y. C.S. S.D. D.C. D.F. Q.L. K.Q. and Y.D. conducted the experiments; X.M. Q.N. A.A.I. A.W. M.A.R. L.A.D.C. C.S.M. W.Z. T.O. S.L. F.R.K. Y.D. S.S.R. G.D.M. and H.F. participated in data analysis and interpretation; X.M. Q.N. A.A.I. G.B.M. F.R.K. Y.D. and H.F. participated in discussion and manuscript preparation; X.M. Q.N. A.A.I. D.C. Y.D. and H.F. designed the experiments and wrote the paper; and all were involved in manuscript editing. H.F. is scientific founder of PiVista Therapeutics. Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",
year = "2022",
month = may,
day = "26",
doi = "10.1016/j.cell.2022.04.014",
language = "English (US)",
volume = "185",
pages = "1974--1985.e12",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "11",
}