Abstract
The HSF1 transcription factor is an integrator of the cellular stress response, and its expression has demonstrated poor prognosis in multiple myeloma. The novel anti-HSF1 small-molecule inhibitors CCT251236 and KRIB11 demonstrate in vitro and in vivo antimyeloma activity, representing a novel approach for targeting the heat shock response in myeloma. Clin Cancer Res; 24(10); 2237–8. ©2018 AACR.
See related article by Fok et al., p. 2395
In this issue of Clinical Cancer Research, Fok and colleagues (1) describe a key role for HSF1 in multiple myeloma cell survival. The HSF1 transcription factor is a key integrator of the cellular stress response, coordinating the expression of chaperone genes, ubiquitin, and heat shock genes (2). HSF1 is localized in the cytoplasm as an inactive monomer. Upon exposure to stress, HSF1 translocates into the nucleus, where it becomes a trimer, gets phosphorylated, and binds heat shock response elements in the promoter of heat shock genes, such as HSPA1A/HSP70.1, HSPC/HSP90, and HSPB1/HSP27 (2). Chromatin immunoprecipitation sequencing (ChIP-Seq) has identified HSF1 target genes beyond heat shock response genes involved in diverse oncogenic processes, including cell-cycle regulation, mitosis, and translation (2).
Multiple myeloma is a plasma cell malignancy characterized by a relapsing clinical course. Neoplastic plasma cells experience proteotoxic stress due to increased immunoglobulin production. Impaired protein homeostasis activates adaptive mechanisms for myeloma cell survival, such as the unfolded protein response and modulation of the heat shock response. HSP90 has been previously demonstrated to be vital for myeloma cell survival via regulation of critical signaling pathways, including MAP kinase, IGFR, and IL6. However, clinical trials testing inhibition of the stress response pathway using HSP90 inhibitors have had limited success in myeloma. Tanespimycin (17-allylamino-17-demethoxygeldanamycin, 17-AAG) demonstrated an overall response rate of 27% in combination with bortezomib in a phase II study in patients with relapsed multiple myeloma (3). Similarly, NVP-AUY922 (luminespib), an inhibitor of HSP90–ATP binding demonstrated disease stabilization in two thirds of the patients but was not developed further due to ocular toxicity (4). More recently, KW-2478, a novel non-ansamycin Hsp90 inhibitor, showed an overall response rate of 39.2% in combination with bortezomib in a phase II trial of 79 patients. The median progression-free survival (PFS) was 6.8 [95% confidence interval (CI), 5.9–not reached (NR)] months, and median duration of response was 5.6 (95% CI, 4.9–NR) months (5).
Using RNAi, the authors demonstrate that HSF1 depletion in vitro decreases the expression of heat shock–related target genes in multiple myeloma cell lines. This is further associated with activation of the unfolded protein response, increased eIF2α phosphorylation, decreased protein synthesis, and apoptotic cell death. Next, they compare the in vitro and in vivo activity of two previously described anti-HSF1 small-molecule inhibitors: CCT251236 and KRIB11. CCT251236 was identified in a screen of compounds preventing stress-induced activation of HSP72, whereas KRIB11 blocks recruitments of HSF1 cofactor p-TEFb to target gene promoters (see Fig. 1). Both compounds phenocopy the effects of HSF1 depletion by shRNA and critically demonstrate primary myeloma cell killing and cytotoxicity in stromal coculture, suggesting that these small molecules may overcome the protective effects of the bone microenvironment in myeloma. Single-agent in vivo efficacy in xenograft models was modest and may be due to constitutive expression of heat shock proteins in vivo. However, the efficacy of HSF1 inhibition may be further improved by rational combination therapy with drugs such as proteasome inhibitors or novel agents such as PERK inhibitors for in vivo application.
The novel HSF1 inhibitors described in this study represent a fresh approach to target the heat shock response pathway in myeloma. The authors have examined several public datasets to demonstrate that expression of HSF1 and its transcriptional target genes are associated with poor prognosis in myeloma, suggesting that there may be a subset of patients with myeloma who could be identified to benefit specifically from this approach. Thus, it will be important to develop biomarkers to identify these patients in future clinical trials examining safety and efficacy of HSF1 inhibition in the current era of personalized therapy for myeloma.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.