Protein modifications drive lung cancer resistance

Key protein modifications such as glycosylation and phosphorylation regulate a variety of cellular processes, such as cell-cell recognition, immune response and cell growth. Dysregulation of these tags is linked to human diseases, making them important to study disease progression and identify biomarkers and druggable targets using mass spectrometry. However, since these modifications are often low-abundance and dynamically modified, they need to be enriched first. Despite the progress in the development of individual enrichment strategies, scientists have yet to develop a highly sensitive and robust platform to focus on multiple modifications simultaneously.

Yu-Ju Chen’s team from Taiwan published an article in the Molecular & Cellular Proteomics introducing a streamlined enrichment strategy called Fe-ZIC-cHILIC, which captures both glycopeptides, or GPs, and phosphopeptides, or PPs, in a single step. This method uses a tandem tip that is packed with a special material combining iron ions with ZIC-cHILIC resin. In this setup, the sample flows through this tandem tip, minimizing protein loss and enriching GPs in the top tip while PPs are in the bottom tip. Using this strategy, they analyzed nonsmall cell lung cancer cells, or NSCLC cells with mutations in the EGFR gene, which is the first-line targeted therapy yet eventually drives drug resistance and leads to tumor recurrence. Within a single cell type, they identified 10,536 GPs and 11,329 PPs and found significant changes on the site-specific glycopeptides and phosphoptpides between drug-sensitive and drug-resistant cells. Notably, they observed changes in EGFR, ERBB2, MET and integrin family proteins, which are primary targets for cancer treatments.

This study highlights both the novelty of Fe-ZIC-cHILIC material in dual enrichment with high specificity to study protein modifications. Further investigations will assess the strategy in different sample types to determine how these modifications drive resistance and how therapies could be developed to improve outcomes.