Histone deacetylase activity mediates acquired resistance towards structurally diverse HSP 90 inhibitors

Heat shock protein 90 ( HSP 90) regulates multiple signalling pathways critical for tumour growth. As such, HSP 90 inhibitors have been shown to act as effective anticancer agents in preclinical studies but, for a number of reasons, the same effect has not been observed in the clinical trials to date. One potential reason for this may be the presence of de novo or acquired resistance within the tumours. To investigate mechanisms of resistance, we generated resistant cell lines through gradual dose escalation of the HSP 90 inhibitor 17‐allylamino‐17‐demethoxygeldanamycin (17‐ AAG ). The resultant resistant cell lines maintained their respective levels of resistance (7–240×) in the absence of 17‐ AAG and were also cross‐resistant with other benzoquinone ansamycin HSP 90 inhibitors. Expression of members of the histone deacetylase family ( HDAC 1, 5, 6) was altered in the resistant cells. To determine whether HDAC activity contributed to resistance, pan‐ HDAC inhibitors ( TSA and LBH 589) and the class II HDAC ‐specific inhibitor SNDX 275 were found to resensitize resistant cells towards 17‐ AAG and 17‐dimethylaminoethylamino‐17‐demethoxygeldanamycin. Most significantly, resistant cells were also identified as cross‐resistant towards structurally distinct HSP 90 inhibitors such as radicicol and the second‐generation HSP 90 inhibitors CCT 018159, VER 50589 and AUY 922. HDAC inhibition also resensitized resistant cells towards these classes of HSP 90 inhibitors. In conclusion, we report that prolonged 17‐ AAG treatment results in acquired resistance of cancer cells towards not just 17‐ AAG but also to a spectrum of structurally distinct HSP 90 inhibitors. This acquired resistance can be inhibited using clinically relevant HDAC inhibitors. This work supports the potential benefit of using HSP 90 and HDAC inhibitors in combination within the clinical setting.