Cancer Conformational Landscape Shapes Tumorigenesis

During tumorigenesis, DNA mutations in protein coding sequences canalter amino acid sequences which can change the structures of proteins. While the 3Dstructure of mutated proteins has been studied with atomic resolution, the preciseimpact of somatic mutations on the 3D proteome during malignant transformationremains unknown because methods to revealin vivoprotein structures in highthroughput are limited. Here, we measured the accessibility of the lysine epsilon-amine forchemical modification across proteomes using covalent protein painting (CPP) toindirectly determine alterations in the 3D proteome. CPP is a novel, high-throughputquantitative mass spectrometric method that surveyed a total of 8052 lysine sites acrossthe 60 cell lines of the well-studied anticancer cell line panel (NCI60). Overall, 5.2structural alterations differentiated any cancer cell line from the other 59. Structuralaberrations in 98 effector proteins correlated with the selected presence of 90 commonly mutated proteins in the NCI60 cell linepanel, suggesting that different tumor genotypes reshape a limited set of effector proteins. We searched our dataset for druggableconformational aberrations and identified 49 changes in the cancer conformational landscape that correlated with the growthinhibition profiles of 300 drug candidates out of 50,000 small molecules. We found that alterations in heat shock proteins are keypredictors of anticancer drug efficacy, which implies that the proteostasis network may have a general but hitherto unrecognized rolein maintaining malignancy. Individual lysine sites may serve as biomarkers to guide drug selection or may be directly targeted foranticancer drug development

Automated summary

This study used a novel high-throughput mass spectrometric method to indirectly measure the accessibility of lysine ε-amine for chemical modification in the proteome, and determined the changes in the 3D proteome during malignant transformation. The results showed that different tumor genotypes reshape a limited set of effector proteins, and alterations in heat shock proteins are key predictors of anticancer drug efficacy.