gms | German Medical Science

Objective: One of the most common genomic alterations in Glioblastoma multiforme (GBM) is the overexpression/amplification of the epidermal growth factor receptor (EGFR) gene, which is detectable in 40-60% of all GBM. Therefore, EGFR is a promising target in GBM therapy, although EGFR-directed antibodies as well as tyrosine kinase inhibitors did not yield the desired results. Since chromatin modification, especially histone deacetylases (HDACs), may control EGFR expression, we combined anti-EGFR and anti-HDAC approaches to investigate the benefit of a combinatorial therapy in glioblastoma cells.

Method: A large panel of highly representative in vitro models of natively EGFR-amplified and EGFRvIII-positive glioblastoma cell lines and non-amplified glioblastoma cell lines were treated either with HDAC-inhibitors alone or in combination with the EGFR tyrosine kinase inhibitor Erlotinib. Moreover, proliferation and migration, as well as EGFR-dependent downstream signaling were determined.

Results: Inhibition of HDAC activity (by SAHA, Scriptaid, CUDC907, MS275 and TSA) reduced proliferation and migration of GBM cell lines irrespective of their EGFR status. Moreover, the combined inhibition of HDACs and EGFR (by HDAC inhibitors in combination with Erlotinib or by the HDAC/EGFR inhibitor CUDC101) additively decreased proliferation and migration of GBM cells, especially of EGFR-amplified cells. Interestingly, even in Erlotinib resistant GBM cells, HDAC inhibition significantly decreased proliferation and migration and partially restored sensitivity to Erlotinib. Furthermore, after HDAC-inhibitor treatment the amount of acetylated histones was increased and the overall expression of EGFR as well as of EGFRvIII was reduced at the protein level, providing a possible explanation for increased sensitivity of EGFR-amplified cells towards HDAC inhibitors.

Conclusions: The combined inhibition of HDACs and EGFR shows additive anti-proliferative and anti-migratory potential in a preclinical model for EGFR-amplified GBM. It is important to note that HDAC inhibition can overcome Erlotinib resistance in EGFR-amplified GBM. In summary, HDAC inhibitors may serve as a new class of potential therapeutics for newly diagnosed tumors in combination with anti-EGFR therapy approaches even in GBM that are treatment-refractory so far.