Cancer Conformational Landscape Shapes Tumorigenesis
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Updated: Sep 30, 2025
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Casimir Bamberger1, Jolene Diedrich1, Salvador Martìnez-Bartholomé1
1Department of Molecular Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
Abstract:
During tumorigenesis, DNA mutations in protein coding sequences can alter amino acid sequences which can change the structures of proteins. While the 3D structure of mutated proteins has been studied with atomic resolution, the precise impact of somatic mutations on the 3D proteome during malignant transformation remains unknown because methods to reveal in vivo protein structures in high throughput are limited. Here, we measured the accessibility of the lysine ε-amine for chemical modification across proteomes using covalent protein painting (CPP) to indirectly determine alterations in the 3D proteome. CPP is a novel, high-throughput quantitative mass spectrometric method that surveyed a total of 8052 lysine sites across the 60 cell lines of the well-studied anticancer cell line panel (NCI60). Overall, 5.2 structural alterations differentiated any cancer cell line from the other 59. Structural aberrations in 98 effector proteins correlated with the selected presence of 90 commonly mutated proteins in the NCI60 cell line panel, suggesting that different tumor genotypes reshape a limited set of effector proteins. We searched our dataset for druggable conformational aberrations and identified 49 changes in the cancer conformational landscape that correlated with the growth inhibition profiles of 300 drug candidates out of 50,000 small molecules. We found that alterations in heat shock proteins are key predictors of anticancer drug efficacy, which implies that the proteostasis network may have a general but hitherto unrecognized role in maintaining malignancy. Individual lysine sites may serve as biomarkers to guide drug selection or may be directly targeted for anticancer drug development.
Insights
Cancer mutations alter protein 3D structures. Covalent protein painting (CPP) reveals these proteome-wide changes, identifying potential drug targets and biomarkers for cancer therapy.
Area of Science:
- Biochemistry
- Proteomics
- Cancer Biology
Background:
- Somatic mutations during tumorigenesis alter protein amino acid sequences, potentially changing protein 3D structures.
- Understanding the impact of these mutations on the 3D proteome in vivo is challenging due to limited high-throughput methods for protein structure determination.
- The NCI60 cancer cell line panel is a well-established resource for anticancer drug screening and understanding cancer biology.
Purpose of the Study:
- To develop and apply a novel high-throughput method to indirectly determine alterations in the 3D proteome across cancer cell lines.
- To identify structural aberrations in proteins that correlate with common cancer mutations.
- To discover druggable conformational aberrations and their association with anticancer drug efficacy.
Main Methods:
- Utilized covalent protein painting (CPP), a quantitative mass spectrometry-based technique, to measure lysine ε-amine accessibility across proteomes.
- Applied CPP to 8052 lysine sites across the 60 cell lines of the NCI60 panel.
- Correlated identified structural aberrations with known mutation data and drug sensitivity profiles.
Main Results:
- Identified an average of 5.2 significant structural alterations differentiating each cancer cell line from others.
- Found that 98 specific effector proteins exhibited structural aberrations linked to 90 commonly mutated proteins in the NCI60 panel.
- Discovered 49 druggable conformational aberrations correlating with growth inhibition profiles of 300 drug candidates, with heat shock protein alterations predicting anticancer drug efficacy.
Conclusions:
- Different tumor genotypes reshape a limited set of effector proteins, impacting the overall 3D proteome.
- The proteostasis network plays a significant, previously unrecognized role in maintaining malignancy.
- Individual lysine sites can serve as potential biomarkers for guiding drug selection or as direct targets for novel anticancer drug development.
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