Histone deacetylase activity mediates acquired resistance towards structurally diverse HSP90 inhibitors

Abstract

Heat shock protein 90 (HSP90) regulates multiple signalling pathways critical for tumour growth. As such, HSP90 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 HSP90 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 HSP90 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 LBH589) and the class II HDAC‐specific inhibitor SNDX275 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 HSP90 inhibitors such as radicicol and the second‐generation HSP90 inhibitors CCT018159, VER50589 and AUY922. HDAC inhibition also resensitized resistant cells towards these classes of HSP90 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 HSP90 inhibitors. This acquired resistance can be inhibited using clinically relevant HDAC inhibitors. This work supports the potential benefit of using HSP90 and HDAC inhibitors in combination within the clinical setting.

Inhibitors of HSP90 in melanoma

“…17-AG enhanced activity of MAPK pathway inhibitors, vemurafenib and trametinib, in induction of apoptosis that might result from concurrent inhibition of IRE1α and ERK1/2 activities [89]. Interestingly, it was also demonstrated that prolonged treatment with 17-AAG could develop resistance to a spectrum of structurally distinct inhibitors of HSP90, and acquired resistance could be overcome by HDAC inhibitors [109].…”

HSF1: Primary Factor in Molecular Chaperone Expression and a Major Contributor to Cancer Morbidity

“…CD44+/Sca1+ cells that were shown to have enhanced radioresistance and increased HSF1 activity were also found to be induced after radiation treatment [107,153,154]. HSF1 may coordinate resistant cancer cell properties through chromatin organization in cooperation with HDACs or other DNA-modifying complexes, such as MTA1, each of which have also been linked to resistance to cytotoxic compounds [155,156]. Alternatively, HSF1 has also been shown to promote resistance to cytotoxic therapies through its pro-glycolysis metabolic regulatory activities [51].…”

BAG3‐dependent expression of Mcl‐1 confers resistance of mutant KRAS colon cancer cells to the HSP90 inhibitor AUY922

“…However, only transient responses to HSP90 inhibitors have been observed in patients with mutant KRAS tumors . This is suggestive of the development of acquired resistance to HSP90 inhibitors by cancer cells . Various mechanisms have been reported to be involved in acquired resistance of cancer cells to HSP90 inhibition .…”

“…This is suggestive of the development of acquired resistance to HSP90 inhibitors by cancer cells . Various mechanisms have been reported to be involved in acquired resistance of cancer cells to HSP90 inhibition . For example, reactivation of the ERK‐p90RSK‐mTOR signalling pathway mediates acquired resistance of KRAS mutant non‐small cell lung cancer (NSCLC) to the HSP90 inhibitor ganetespib, whereas the secondary Y142N mutation in HSP90α confers acquired resistance of MDA‐MB‐231 breast cancer cells to the HSP90 inhibitor PU‐H71 .…”

“…12 Various mechanisms have been reported to be involved in acquired resistance of cancer cells to HSP90 inhibition. [12][13][14][15] For example, reactivation of the ERK-p90RSK-mTOR signalling pathway mediates acquired resistance of KRAS mutant non-small cell lung cancer (NSCLC) to the HSP90 inhibitor ganetespib, 14 whereas the secondary Y142N mutation in HSP90α confers acquired resistance of MDA-MB-231 breast cancer cells to the HSP90 inhibitor PU-H71. 13 It seems that resistance mechanisms to HSP90 inhibition may vary considerably depending on cell types and inhibitors in question.…”