Inhibiting Heat Shock Factor 1 in Cancer: A Unique Therapeutic Opportunity

• Published in: Trends in pharmacological sciences (Regular ed.) Vol. 40; no. 12; pp. 986 - 1005
• Main Authors: Dong, Bushu, Jaeger, Alex M., Thiele, Dennis J.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.12.2019
• Subjects: inhibitors; non-oncogene addiction; stress protection; inhibitors; stress protection; non-oncogene addiction
• ISSN: 0165-6147; 1873-3735
• DOI: 10.1016/j.tips.2019.10.008

The ability of cancer cells to cope with stressful conditions is critical for their survival, proliferation, and metastasis. The heat shock transcription factor 1 (HSF1) protects cells from stresses such as chemicals, radiation, and temperature. These properties of HSF1 are exploited by a broad spectrum of cancers, which exhibit high levels of nuclear, active HSF1. Functions for HSF1 in malignancy extend well beyond its central role in protein quality control. While HSF1 has been validated as a powerful target in cancers by genetic knockdown studies, HSF1 inhibitors reported to date have lacked sufficient specificity and potency for clinical evaluation. We review the roles of HSF1 in cancer, its potential as a prognostic indicator for cancer treatment, evaluate current HSF1 inhibitors and provide guidelines for the identification of selective HSF1 inhibitors as chemical probes and for clinical development. Heat shock transcription factor 1 (HSF1) is a pivotal protein for cellular stress protection in response to a variety of environmental insults and physiological stresses.The prosurvival and other key functions of HSF1 have been exploited by a surprisingly broad spectrum of human malignancies to support cancer cell survival, proliferation, invasion, and metastasis.The functional importance of HSF1 in cancer extends far beyond its classical role in protein homeostasis, revealing unique opportunities for targeting HSF1 as a novel cancer therapy.Insights into the specificity and mechanism of action of current HSF1 inhibitors, and concepts for the identification and validation of bona fide HSF1 inhibitors, will be important to advance HSF1 as a therapeutic target.