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Author Notes:

Haian Fu, Ph.D, hfu@emory.edu

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.

This work was supported by NCI’s Cancer Target Discovery and Development (CTD2) Network (U01CA217875 to HF; U01CA217842 to GBM). 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 (SR, HF; P50CA217691) Career Enhancement Program (XM and AAI, P50CA217691), Winship Cancer Institute (NIH 5P30CA138292), 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 GBM.

H.F. is scientific founder of PiVista Therapeutics.

Subjects:

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Biochemistry & Molecular Biology
  • Cell Biology
  • KINASE
  • PATHWAY
  • ACTIVATION
  • REVEALS
  • AKT1
  • NRF2
  • BRAF
  • ATM

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

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Journal Title:

CELL

Volume:

Volume 185, Number 11

Publisher:

, Pages 1974-+

Type of Work:

Article | Post-print: After Peer 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.

Copyright information:

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/).
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