Effect of the histone deacetylase inhibitor LBH589 against epidermal growth factor receptor–dependent human lung cancer cells

Abstract

Activating mutations in the epidermal growth factor receptor (EGFR) selectively activate signal transducers and activators of transcription (STAT) and Akt survival signaling pathways important in lung cancer cell growth and survival. Many kinases, such as EGFR, rely on heat shock protein 90 (Hsp90) chaperone function for conformational maturation and proper function. Histone deacetylase inhibitors (HDACi) have been suggested to regulate signaling protein interactions via modulation of protein chaperone function through Hsp90. For these reasons, we evaluated the effect of a HDACi in lung cancer cells with defined EGFR status. Cell lines with defined EGFR status and sensitivity to EGFR tyrosine kinase inhibitors were exposed to the HDACi LBH589, and the effects on cell survival, proliferation, and downstream signaling were evaluated. LBH589 resulted in increased acetylation of Hsp90 and reduced association of Hsp90 with EGFR, Akt, and STAT3. LBH589 selectively depleted proteins important in signaling cascades in cell lines harboring EGFR kinase mutations, such as EGFR, STAT3, and Akt, and these cells underwent apoptosis following exposure to LBH589. In addition, we found depletion of STAT3-dependent survival proteins, including Bcl-xL, Mcl-1, and Bcl-2. Conversely, LBH589 had little effect on apoptosis in cells not dependent on EGFR for survival, no changes were identified in the expression of EGFR or other survival proteins, and the predominant effect was cell cycle arrest rather than apoptosis. A 10-fold increase in LBH589 was necessary to observe durable depletion of EGFR and Akt in cells not harboring EGFR mutation. Treatment of cells with erlotinib and LBH589 resulted in synergistic effects on lung cancer cells dependent on EGFR for growth and/or survival. Based on these results, LBH589 can acetylate Hsp90, deplete EGFR and other key survival signaling proteins, and trigger apoptosis only in lung cancer cells harboring EGFR mutations. Therefore, EGFR mutation status may be predictive of outcome with LBH589 and possibly other HDACi. [Mol Cancer Ther 2007;6(9):2515 -24]

Combinations of DNA Methyltransferase and Histone Deacetylase Inhibitors Induce DNA Damage in Small Cell Lung Cancer Cells: Correlation of Resistance with IFN-Stimulated Gene Expression

“…2). Despite evidence that apoptosis induced by HDAC inhibitors can be increased by 5-AZA-dC (16,21,39), our data suggested that induction of apoptosis was not the primary mechanism for synergy between 5-AZA-dC and MGCD0103 in SCLC cells.…”

WZ4002, a third-generation EGFR inhibitor, can overcome anoikis resistance in EGFR-mutant lung adenocarcinomas more efficiently than Src inhibitors

“…HDAC inhibitors have proapoptotic effects on quiescent cancer stem cells or slowly cycling cells that often resist therapy and serve as the source of relapse by reducing Wnt signaling, which has a critical role in stem cell maintenance, or by inhibiting the chaperone function of heat shock protein 90. 13,31,32 Our results suggest that H1975 SR cells have slowly growing subpopulations that are sensitive to HDAC inhibitors. However, the molecular mechanisms underlying the proapoptotic effect of TSA on these subpopulations in H1975 SR cells remain to be elucidated.…”

“…29 Moreover, a report showed that HDAC inhibitors synergistically enhanced the levels of EGFR TKI-induced apoptosis in EGFR-mutant lung adenocarcinoma cell lines. 31 Therefore, it seems reasonable that suspended HCC827 cells were highly vulnerable to the combined treatment with WZ4002, ABT-263 with or without TSA, and consequently resulted in almost complete cell death by the long-term combination therapy (Figure 6d). On the other hand, H1975 SR cells are likely to have subpopulations that can evade apoptosis induced by the combination therapy of WZ4002 and ABT-263, and these subpopulations of cells seem to be susceptible to TSA (Figure 6d and e).…”

Synthesis and Biological Evaluation of 1-(2-Aminophenyl)-3-arylurea Derivatives as Potential EphA2 and HDAC Dual Inhibitors

“…22) HDAC inhibitors have been shown to synergize with other agents, including RTK inhibitors, to suppress proliferation and induce apoptosis in tumor cells. 23,24) This evidence suggests that simultaneous EphA2 activation and HDAC inhibition could be a promising approach in cancer therapy. Here, compound N-(4-(3-(2-aminophenyl) ureido) phenyl)-4-methylbenzamide (5e) was disclosed to inhibit EphA2 and HDAC based on the virtual screening.…”