TRAP1: a viable therapeutic target for future cancer treatments?

ABSTRACT

Introduction: HSP90 molecular chaperones (i.e., HSP90α, HSP90β, GRP94 and TRAP1) are potential therapeutic targets to design novel anticancer agents. However, despite numerous designed HSP90 inhibitors, most of them have failed due to unfavorable toxicity profiles and lack of specificity toward different HSP90 paralogs. Indeed, a major limitation in this field is the high structural homology between different HSP90 chaperones, which significantly limits our capacity to design paralog-specific inhibitors.

Area covered: This review examines the relevance of TRAP1 in tumor development and progression, with an emphasis on its oncogenic/oncosuppressive role in specific human malignancies and its multifaceted and context-dependent functions in cancer cells. Herein, we discuss the rationale for considering TRAP1 as a potential molecular target and the strategies used to date, to achieve its compartmentalized inhibition directly in mitochondria.

Expert opinion: TRAP1 targeting may represent a promising strategy for cancer therapy, based on the increasing and compelling evidence supporting TRAP1 involvement in human carcinogenesis. However, considering the complexity of TRAP1 biology, future strategies of drug discovery need to improve selectivity and specificity toward TRAP1 respect to other HSP90 paralogs. The characterization of specific human malignancies suitable for TRAP1 targeting is also mandatory.

KEYWORDS:

• Cancer
• endoplasmic reticulum
• HSP90
• mitochondria
• molecular chaperone
• protein quality control
• TRAP1
• tumor metabolism

Article highlights

• HSP90 chaperones are critical in tumor cell response/adaptation to stress conditions, thus playing a key role in cell proliferation, motility, angiogenesis and metastasis.

• TRAP1 is a component of the HSP90 family responsible for protection from apoptosis and drug resistance, regulation of cell proliferation and protein homeostasis. TRAP1 contributes to tumor cell bioenergetics, regulating the balance between oxidative metabolism and glycolysis in a context-dependent manner.

• TRAP1 plays different roles (oncogenic versus oncosuppressive) in human malignancies depending on tumor type and environmental context.

• Both HSP90 and TRAP1 have been envisioned as potential targets for anticancer strategies. However, low efficacy and toxicity issues have limited the therapeutic use of HSP90 inhibitors and this likely depends on the lack of specificity of the current generations of inhibitors that target all HSP90 isoforms.

• The design of TRAP1-specific inhibitors has been based, so far, on its prevalent mitochondrial compartmentalization, as a rationale to improve selectivity and specificity of action respect to other HSP90 inhibitors. The recent description of the crystal structure of human TRAP1 will likely boost the design of new compounds that selectively inactivate TRAP1.

• Future clinical development of TRAP1 targeting strategies needs to take in account that its inhibition may be beneficial depending on tumor types/contexts and specific biomarkers are required to select tumors suitable for TRAP1 inhibition.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This work was supported by AIRC (Grant IG2015 Id.16738 to M. Landriscina and F. Esposito and Grant IG16977 to M.P. Costi) and the University of Foggia (PRA Grant to M. Landriscina).