HSF1 Is Essential for Myeloma Cell Survival and A Promising Therapeutic Target.
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Date
2018-05-15ICR Author
Author
Fok, JHL
Hedayat, S
Zhang, L
Aronson, LI
Mirabella, F
Pawlyn, C
Bright, MD
Wardell, CP
Keats, JJ
De Billy, E
Rye, CS
Chessum, NEA
Jones, K
Morgan, GJ
Eccles, SA
Workman, P
Davies, FE
Type
Journal Article
Metadata
Show full item recordAbstract
Purpose: Myeloma is a plasma cell malignancy characterized by the overproduction of immunoglobulin, and is therefore susceptible to therapies targeting protein homeostasis. We hypothesized that heat shock factor 1 (HSF1) was an attractive therapeutic target for myeloma due to its direct regulation of transcriptional programs implicated in both protein homeostasis and the oncogenic phenotype. Here, we interrogate HSF1 as a therapeutic target in myeloma using bioinformatic, genetic, and pharmacologic means.Experimental Design: To assess the clinical relevance of HSF1, we analyzed publicly available patient myeloma gene expression datasets. Validation of this novel target was conducted in in vitro experiments using shRNA or inhibitors of the HSF1 pathway in human myeloma cell lines and primary cells as well as in in vivo human myeloma xenograft models.Results: Expression of HSF1 and its target genes were associated with poorer myeloma patient survival. ShRNA-mediated knockdown or pharmacologic inhibition of the HSF1 pathway with a novel chemical probe, CCT251236, or with KRIBB11, led to caspase-mediated cell death that was associated with an increase in EIF2α phosphorylation, CHOP expression and a decrease in overall protein synthesis. Importantly, both CCT251236 and KRIBB11 induced cytotoxicity in human myeloma cell lines and patient-derived primary myeloma cells with a therapeutic window over normal cells. Pharmacologic inhibition induced tumor growth inhibition and was well-tolerated in a human myeloma xenograft murine model with evidence of pharmacodynamic biomarker modulation.Conclusions: Taken together, our studies demonstrate the dependence of myeloma cells on HSF1 for survival and support the clinical evaluation of pharmacologic inhibitors of the HSF1 pathway in myeloma. Clin Cancer Res; 24(10); 2395-407. ©2018 AACRSee related commentary by Parekh, p. 2237.
Subject
Cell Line, Tumor
Animals
Humans
Mice
Multiple Myeloma
Disease Models, Animal
Caspases
Antineoplastic Agents
Xenograft Model Antitumor Assays
Gene Expression Profiling
Computational Biology
Signal Transduction
Apoptosis
Cell Survival
Gene Knockdown Techniques
Kaplan-Meier Estimate
Molecular Targeted Therapy
Biomarkers, Tumor
Heat Shock Transcription Factors
Research team
Medicinal Chemistry 3
Myeloma Biology and Therapeutics
Myeloma Target Treatment
Functional Genomics
Language
eng
Date accepted
2017-12-29
License start date
2018-05
Citation
Clinical cancer research : an official journal of the American Association for Cancer Research, 2018, 24 (10), pp. 2395 - 2407
Publisher
AMER ASSOC CANCER RESEARCH