Enhancing proteotoxic stress in leiomyosarcoma cells triggers mitochondrial dysfunctions, cell death and anti-tumor activity in vivo.

Leiomyosarcomas (LMS) are rare and aggressive tumors characterized by a complex karyotype. Surgical resection with or without radiotherapy and chemotherapy is the standard curative treatment. Unfortunately, a high percentage of LMS recurs and metastasizes. In these cases, doxorubicin and ifosfamide represent the standard treatment but with low response rates. Here, we evaluated the induction of proteotoxic stress as a possible strategy to kill LMS cells in a therapeutic perspective. We show that aggressive LMS coexist with high levels of proteotoxic stress. As a consequence, we hypothesized that LMS cells are vulnerable to further increases of proteotoxic stress. The small compound 2c is a strong inducer of proteotoxic stress. In LMS cells, it triggers cell death coupled to a profound re-organization of the mitochondrial network. By using STED microscopy, we have unveiled the existence of DIABLO/SMAC clusters that are modulated by 2c. Finally, we have engineered a new version of 2c linked to PEG though a short peptide, named 2cPP. This new pro-drug is specifically activated by proteases present in the tumor microenvironment. 2cPP shows a strong anti-tumor activity in vivo against LMS and no toxicity against normal cells.