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Untangling TKI resistance in lung cancer

Written by Charlotte Harrison, Science Writer

Non-small cell lung cancer (NSCLC) is often associated with activating mutations in receptor tyrosine kinases that drive cancer progression and resistance to targeted tyrosine kinase inhibitors (TKIs).

With the aim of better upstanding TKI resistance, researchers from Georgetown University, University of Montana and collaborators studied large-scale post-translational modification (PTM) data to find cell signalling pathways that were modulated by TKIs in NSCLC cells. Their findings could help develop new drug combinations for cancer therapy.

 Working out connections

The 10 analysed NSCLC cell lines had driver mutations in EGFR, ALK, ERBB2/HER2, ROS1 and DDR2, and were treated with 4 TKIs – erlotinib, crizotinib afatinib and dasatinib. The researchers used network-based approaches to analyse protein phosphorylation, acetylation, and ubiquitination in the treated cell lines to model cell signalling pathways.

They then used a novel strategy in which curated pathways from NCATS BioPlanet were used to identify interactions among cell signalling pathways that were supported by their own PTM data. By using this approach, they obtained a high-level overview of connections between specific pathways and cellular mechanisms.

These connections were then incorporated with the authors’ model, to form an integrated model that focused on interactions between pathways that did not have proteins in common but likely had a relationship, as indicated by PTM patterns.

New insights

The integrated model afforded several new insights into the response of lung cancer cells to TKIs. For example, the researchers showed that there is crosstalk between pathways involving EGFR and ALK and pathways involving glycolysis and gluconeogenesis, and the transmembrane transport of small molecules.

They also unearthed previously unappreciated connections between receptor tyrosine kinase signal transduction and oncogenic metabolic reprogramming.

Furthermore, they identified a common core of protein–protein interactions that involved heat shock/chaperone proteins, metabolic enzymes, cytoskeletal components, and RNA-binding proteins.

These findings of how pathways and proteins connect in treated NSCLC could have therapeutic relevance (after further study); “elucidation of points of crosstalk among signalling pathways employing different PTMs reveals new potential drug targets and candidates for synergistic attack through combination drug therapy,” said the authors.