Phosphoproteome networks identify focal adhesion kinase as a new drug target that can be exploited in synergistic combination with paclitaxel

Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with a 5-year survival of 7.7%.[1] Treatment with cytotoxic agents extends life expectancy by a few months.[2] To improve this poor outcome new drug regimens against key features of PDAC's deadly behavior are urgently warranted. This study is the first to employ phosphotyrosine-based kinase screens on (pre)clinical PDAC models and tissues to understand the aggressive nature and identify new drug targets. Methods: We performed phosphoproteomics on 11 PDAC cell lines, 7 primary cell cultures, 10 patient-derived xenografts (PDX) and 16 human tumors. Tyrosine phosphopeptides were enriched by immunoprecipitation and analyzed by mass spectrometry. Results: Focal adhesion kinase (FAK) was identified as highly activated and inhibition of this kinase by the tyrosine kinase inhibitor defactinib resulted in reduced proliferation and migration in vitro. Combination with paclitaxel exhibited synergistic lethality. The relevance of FAK was assessed in vivo through analyses of PDX and human tumor kinase phosphoproteomes. This revealed highly similar kinase profiles in the majority of the tumors, highlighting the importance of FAK in PDAC. Conclusion: Our extensive phosphoproteome analyses of PDAC models revealed a key role of FAK, which showed potential as a new drug target, especially in combination with paclitaxel-based drug regimens. Future clinical trials are needed to investigate the effect of this novel treatment on survival of patients suffering from PDAC. References