A Novel Inhibitor of HSP70 Induces Mitochondrial Toxicity and Immune Cell Recruitment in Tumors

Cancer Res. 2020 Dec 1;80(23):5270-5281. doi: 10.1158/0008-5472.CAN-20-0397.

Thibaut Barnoud ¹, Jessica C Leung ^# ¹, Julia I-Ju Leu ^# ², Subhasree Basu ^# ¹, Adi Narayana Reddy Poli ^# ¹, Joshua L D Parris ¹ ³, Alexandra Indeglia ¹ ⁴, Tetyana Martynyuk ¹, Madeline Good ¹, Keerthana Gnanapradeepan ¹ ⁴, Emilio Sanseviero ⁵, Rebecca Moeller ⁶, Hsin-Yao Tang ¹, Joel Cassel ¹, Andrew V Kossenkov ⁷, Qin Liu ¹, David W Speicher ¹, Dmitry I Gabrilovich ³, Joseph M Salvino ⁸, Donna L George ², Maureen E Murphy ⁸

Affiliations

1 Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, Pennsylvania.
2 Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
3 Department of Graduate Group in Cell and Molecular Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
4 Department of Biochemistry and Molecular Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
5 Program in Immunology, Metastasis and Microenvironment, The Wistar Institute, Philadelphia, Pennsylvania.
6 Drexel University College of Medicine, Philadelphia, Pennsylvania.
7 Program in Gene Expression and Regulation, The Wistar Institute, Philadelphia, Pennsylvania.
8 Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, Pennsylvania. mmurphy@wistar.org jsalvino@wistar.org.
# Contributed equally.

PMID: 33023943 DOI: 10.1158/0008-5472.CAN-20-0397

Abstract

The protein chaperone HSP70 is overexpressed in many cancers including colorectal Cancer, where overexpression is associated with poor survival. We report here the creation of a uniquely acting HSP70 Inhibitor (HSP70i) that targets multiple compartments in the Cancer cell, including mitochondria. This inhibitor was mitochondria toxic and cytotoxic to colorectal Cancer cells, but not to normal colon epithelial cells. Inhibition of HSP70 was efficacious as a single agent in primary and metastatic models of colorectal Cancer and enabled identification of novel mitochondrial client proteins for HSP70. In a syngeneic colorectal Cancer model, the inhibitor increased immune cell recruitment into tumors. Cells treated with the inhibitor secreted danger-associated molecular patterns (DAMP), including ATP and HMGB1, and functioned effectively as a tumor vaccine. Interestingly, the unique properties of this HSP70i in the disruption of mitochondrial function and the inhibition of proteostasis both contributed to DAMP release. This HSP70i constitutes a promising therapeutic opportunity in colorectal Cancer and may exhibit antitumor activity against Other tumor types. SIGNIFICANCE: These findings describe a novel HSP70i that disrupts mitochondrial proteostasis, demonstrating single-agent efficacy that induces immunogenic cell death in treated tumors.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-162567

AP-4-139B

Heat Shock Protein 70 Inhibitor

HSP

Cancer

Name
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