Elucidating synergistic dependencies in lung adenocarcinoma by proteome-wide signaling-network analysis

Mukesh Bansal, Jing He, Michael Peyton, Manjunath Kustagi, Archana Iyer, Michael Comb, Michael White, John D Minna and Andrea Califano

PLOS ONE, 2019, vol. 14, issue 1, 1-25

Abstract: To understand drug combination effect, it is necessary to decipher the interactions between drug targets—many of which are signaling molecules. Previously, such signaling pathway models are largely based on the compilation of literature data from heterogeneous cellular contexts. Indeed, de novo reconstruction of signaling interactions from large-scale molecular profiling is still lagging, compared to similar efforts in transcriptional and protein-protein interaction networks. To address this challenge, we introduce a novel algorithm for the systematic inference of protein kinase pathways, and applied it to published mass spectrometry-based phosphotyrosine profile data from 250 lung adenocarcinoma (LUAD) samples. The resulting network includes 43 TKs and 415 inferred, LUAD-specific substrates, which were validated at >60% accuracy by SILAC assays, including “novel’ substrates of the EGFR and c-MET TKs, which play a critical oncogenic role in lung cancer. This systematic, data-driven model supported drug response prediction on an individual sample basis, including accurate prediction and validation of synergistic EGFR and c-MET inhibitor activity in cells lacking mutations in either gene, thus contributing to current precision oncology efforts.

Date: 2019
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pone00:0208646

DOI: 10.1371/journal.pone.0208646

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