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.