Kinom profiling of tyrosine kinases identifies Src-family kinases to be highly activated in HNSCC

Background:

Every year approximately 400,000 patients are diagnosed with HNSCC worldwide. Despite the different therapy options like surgery, radio-/chemotherapy and target therapy using Cetuximab, survival rates are still low. For target therapies, which are meant to inhibit hyperactivated kinases, the major obstacle is the heterogeneity of HNSCC, which has reasonably been characterized only on the level of gene mutation and mRNA expression analysis so far. However, systematic characterization of the kinase activity profile in HNSCC is still, missing although this is the essential parameter for targeted therapy strategies using kinase inhibiting agents.

Methods:

Here performed kinomic profiling studies analysed the activity of tyrosine kinases in tumor tissue and corresponding normal tissue of 16 HPV(-)-HNSCC patients using a high-content phospho-peptide substrate microarray (PamStation®12). The results were validated by direct methods such as Western blot.

Results:

Overall, tumor samples showed a higher activity of tyrosine kinases compared to the corresponding normal tissue. Upstream kinase analysis identified kinases of the Src-family to be highly activated in more than the half of the tumors. Increased Src-activity was validated by Western blot and SH2-profiling. Furthermore, the in vitro testing of Src-specific and non-Src inhibitors confirmed increased Src-acitivty in tumor samples and points on the potential use of the PamStation®12 to predict response towards targeted agents.

Conclusions:

By performing kinomic profiling experiments using the PamStation®12 we newly identified Src family kinases to be frequently upregulated in HNSCC. These results give new insights in HNSCC biology but also highlight Src as a new potential target for precision therapy of HNSCC.

Publication History

Publication Date:
18 April 2018 (online)