A novel inhibitor of HSP70 induces mitochondrial toxicity and immune cell recruitment in tumors.

The protein chaperone HSP70 is overexpressed in many cancers including colorectal cancer (CRC), where overexpression is associated with poor survival. We report here the creation of a uniquely acting HSP70 inhibitor that targets multiple compartments in the cancer cell including mitochondria. This inhibitor was mitochondria-toxic and cytotoxic to CRC cells but not normal colon epithelial cells. Inhibition of HSP70 was efficacious as a single agent in primary and metastatic models of CRC and enabled identification of novel mitochondrial client proteins for HSP70. In a syngeneic CRC 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 HSP70 inhibitor in the disruption of mitochondrial function and the inhibition of proteostasis both contributed to DAMP release. This HSP70 inhibitor constitutes a promising therapeutic opportunity in colorectal cancer and may exhibit anti-tumor activity against other tumor types.