Inhibitors of the Signal Transducer and Activation of Transcription (STAT) Pathway

The STAT pathway is another interesting pathway that can be activated by Src, a nonreceptor cytoplasmic tyrosine kinase that is activated by signals from cell surface receptors, such as EGFR. Different preclinical studies suggested that STAT-3 may be implicated in resistance to radiation and cetuximab (Bonner et al. 2011; Sen et al. 2012). Dasatinib, an inhibitor of c-src, was investigated in vitro. Results showed induction of apoptosis, blockage of DNA repair in EGFR-expressing SCCHN cells, and sensitization of SCCHN cell lines to radiation (Raju et al. 2012). However, single administration of dasatinib failed to demonstrate any clinical activity in patients with advanced SCCHN. Currently a preoperative window study comparing single agent erlotinib or dasatinib to placebo to the combination of both drugs is ongoing (NCT00779389). First results, presented at ASCO 2014 showed that high pMAPK expression was associated with reduced tumor size for patients treated with erlotinib without an independent or added effect of dasatinib (Bauman et al. 2014). Another study with a Src kinase inhibitor Saracatinib, (175 mg daily) had to be stopped earlier than planned due to lack of efficacy (Fury et al. 2011). A preclinical study showed that increased EGFR activation by ligand administration rescued cells from dasatinib-induced apoptosis, whereas inhibition of EGFR enhanced its apoptotic effect (Lin et al. 2012). This could be one possible explication for the poor clinical activity seen with Src inhibitors as monotherapy in SCCHN.

< Prev   CONTENTS   Source   Next >