Histone Deacetylase Inhibitors Resensitize EGFR/EGFRvIII-Overexpressing, Erlotinib-Resistant Glioblastoma Cells to Tyrosine Kinase Inhibition

Abstract

Although the epidermal growth factor receptor (EGFR) is overexpressed and/or amplified in more than 50 % of all glioblastomas (GBM), therapeutic targeting of the EGFR has not yet been successful. Since histone deacetylases (HDAC) have been described as controlling EGFR expression, we combined the EGFR tyrosine kinase inhibitor erlotinib with different HDAC inhibitors (HDACi) and investigated the benefit of combinatorial therapy for glioblastoma cells. Using representative models of EGFR-amplified, erlotinib-sensitive and -resistant GBM with or without EGFRvIII expression, we determined proliferation, migration, and EGFR-dependent signaling in response to erlotinib and HDACi alone or in combination. HDACi significantly inhibited proliferation of erlotinib-resistant GBM cells, partially restored their sensitivity to erlotinib, and also significantly reduced proliferation of all treatment-naïve cell lines tested. In combination with erlotinib, the development of resistance was prevented. The multitargeted EGFR/HDAC-inhibitor CUDC-101 exhibited similar effects. However, inhibition of cell migration was only achieved by targeting EGFR, and HDACi exhibited no additive effect. Mechanistically, we identified an HDACi-dependent decrease of EGFR/EGFRvIII protein expression underlying the anti-proliferative effects of HDACi. In conclusion, HDACi in combination with erlotinib might serve as a treatment option for newly diagnosed, treatment-naïve tumors irrespective of their EGFR status, as well as for treatment-refractory, EGFR-overexpressing GBM.

Belinostat exerts antitumor cytotoxicity through the ubiquitin‐proteasome pathway in lung squamous cell carcinoma

“…We hypothesize that this could indirectly affect expression of SOS. While HDAC inhibitors have been reported to resensitize erlotinib-resistant cells by transcriptionally reducing EGFR expression (Chen et al, 2013;Liffers et al, 2016), SOS mRNA levels were found to be unchanged following the addition of belinostat even though belinostat dose dependently induced acetylation of histones H3 and H4 (Fig. S5).…”

HDACs and HDAC Inhibitors in Cancer Development and Therapy

“…CUDC-101, with a potent inhibitory activity against EGFR, HER2 and HDACs, is currently being evaluated in clinical trials as a treatment for advanced solid tumors, such as head and neck, gastric, breast, liver and non-small cell lung cancer tumors (Cai et al 2010; Galloway et al 2015). Recent research also indicates the antitumor effect of CUDC-101 in EGFR-overexpressing glioblastoma and anaplastic thyroid cancer (Liffers et al 2015; Zhang et al 2015a). CUDC-907 is another dual-acting agent developed by the same research group to inhibit both HDACs and phosphoinositide 3-kinase (PI3K) (Qian et al 2012) and its clinical trials are underway for the treatment of lymphoma and multiple myeloma as well as advanced/relapsed solid tumors.…”

Epigenetic regulation of RTK signaling

“…Obviously other genes are regulated as well. The discovery of the connections between HDAC activity and cancer have initiated the development of small molecule inhibitors with activity against HDACs [14], and the clinical testing of combined HDAC and RTK pathway inhibition are in progress. Several relevant examples are discussed below (Figure 1).…”