Details

Autor(en) / Beteiligte

• Harrison, Christina
• Wilson, Jennifer L.
• Fraenkel, Ernest
• Herrlich, Andreas
• Lauffenburger, Doug

Titel

Signaling regulators of TGF cleavage predict mechanisms for RTK re‐activation and therapeutic resistance in gastric cancer

Ist Teil von

• The FASEB journal, 2016-04, Vol.30 (S1)

Erscheinungsjahr

2016

Link zum Volltext

Quelle

Wiley Online Library - AutoHoldings Journals

Beschreibungen/Notizen

• Abstract only Alternative growth factor pathway activation causes resistance to targeted receptor tyrosine kinase (RTK) therapies, yet there is little understanding of the intracellular control of this process and how ligand shedding may affect therapeutic response. Already, the EGFR family and multiple matrix metalloproteinases are associated with altered growth and metastasis in gastric cancers, though, we do not know how signaling in these growth pathways may affect resistance. We use a network‐based approach to study the intracellular events affecting alternative pathway activation, specifically investigating the role of TGFα, an EGFR ligand, in gastric cancer. From the network‐based optimization, we identify a list of candidate intracellular targets. We indentified potential targets using randomization and robustness testing and targets were selected as significant if they were consistent in these metrics. While the approach predicts new targets as relevant to ligand shedding and growth factor activation, it does not assign directionality to their potential effects. As such, it is necessary to validate their effects directly. We performed shRNA knockdowns for top targets: GOLGA2, PAK1, and RAB1A and measured their effects on ligand shedding. PAK1 and RAB1 increased ligand shedding in vitro . This shows that PAK1 and RAB1 might be involved in intracellular signaling processes that induce TGFα ligand shedding. To further validate the model, we searched public databases for these targets in patient samples with gastric cancer and in other cancer types. This comparison allows us to better understand mechanisms that may be unique to gastric cancer and what mechanisms might be consistent across cancer types. Through the use of further network analysis and predictive modeling, we have picked additional targets to validate in vitro ; CASP9, RAF1, XIAP, and CFTR. As these additional targets were also not in the original screen, we plan to measure ligand shedding after shRNA knockdown of these genes.