Mechanisms of Resistance to Hsp90 Inhibitor Drugs: A Complex Mosaic Emerges

Abstract

The molecular chaperone Hsp90 holds great promise as a cancer drug target, despite some of the initial clinical trials of Hsp90 inhibitor drugs having not lived up to expectation. Effective use of these drugs will benefit greatly from a much more detailed understanding of the factors that contribute to resistance, whether intrinsic or acquired. We review how cell culture studies have revealed a number of different mechanisms whereby cells can be rendered less susceptible to the effects of Hsp90 inhibitor treatment. A major influence is Hsp90 inhibition causing strong induction of the heat shock response, a stress response that increases cellular levels of prosurvival chaperones such as Hsp27 and Hsp70. Another problem seems to be that these inhibitors do not always access the Hsp90 proteins of the mitochondrion, forms of Hsp90 that—in cancer cells—are operating to suppress apoptosis. It should be possible to overcome these drawbacks through the appropriate drug redesign or with the combinatorial use of an Hsp90 inhibitor with a drug that targets either heat shock factor or the chaperone Hsp70. Still though, cells will often differ in the key antiapoptotic versus proapoptotic activities that are dependent on Hsp90, in the key steps in their apoptotic pathways responsive to Hsp90 inhibition or Hsp70 level, as well as the extents to which their survival is dependent on oncogenic tyrosine kinases that are clients of Hsp90. A systems approach will therefore often be required in order to establish the most prominent effects of Hsp90 inhibition in each type of cancer cell.

Colorectal Cancer Consensus Molecular Subtypes Translated to Preclinical Models Uncover Potentially Targetable Cancer Cell Dependencies

“…HSP90 is a molecular chaperone that maintains the homeostasis of many different client proteins and consequently, HSP90 inhibition may block multiple oncogenic signaling pathways simultaneously (39,44). Several potential mechanisms of resistance have been described, including compensatory up-regulation of heat shock response by the transcription factor HSF1, involving particularly the pro-survival chaperones HSP70 and HSP27 (46). We confirm transcriptional upregulation of heat shock response in CMS4 cell lines after HSP90 inhibition, indicating a specific response to the targeted treatment.…”

Identification of Mixed Lineage Leukemia 1(MLL1) Protein as a Coactivator of Heat Shock Factor 1(HSF1) Protein in Response to Heat Shock Protein 90 (HSP90) Inhibition

“…Consistent with this work, our previous studies indicated that the combined targeting of HSP90 and HSF1-mediated heat shock response could be an effective approach to enhance HSP90 inhibitor activities (13,41). However, the identification of approaches to target HSF1 remains a challenge.…”

Hsp90: Friends, clients and natural foes

“…The phosphorylated Hsp27 has been revealed to stabilize the protein translation factor eIF4E in androgene resistant prostate cancer cells [223]. Phosphorylated Hsp27 has also been involved in metastasis [224]. Recently, it has been shown that HSF-1 is an important facilitator of oncogenesis [221,225].…”