Succinate Dehydrogenase-Deficient Cancer Cells Have Increased Susceptibility to Ym155 Induced DNA Damage

Area of Science:

• Oncology
• Genetics
• Mitochondrial Biology

Background:

• Hereditary pheochromocytoma and paraganglioma (hPPGL) syndrome arises from inherited mutations in Succinate Dehydrogenase genes (SDHx).
• Tumors with Succinate Dehydrogenase subunit B (SDHB) deficiency exhibit heightened metastatic potential, necessitating novel therapeutic strategies.
• Current treatments for SDHB-deficient cancers are largely palliative, highlighting an urgent need for improved therapeutic avenues.

Purpose of the Study:

• To discover novel SDH-dependent, mitochondria-directed cytotoxic agents for treating SDHB-deficient cancers.
• To investigate the potential of mitochondrial ionophores and chemotherapeutic compounds against SDHB-deficient tumor cells.
• To elucidate the mechanism underlying the enhanced sensitivity of SDHB-deficient cells to specific chemotherapeutic agents.

Main Methods:

• Utilized human SDHB-deficient UOK269 RCC cells (SDHB-KO) and isogenic SDHB-reconstituted control cells (SDHB-WT).
• Screened mitochondrial ionophores (2,4-Dinitrophenol, BAM15, Niclosamide, Nitazoxanide) and the chemotherapeutic Ym155 for preferential cytotoxicity.
• Validated findings in primary human pheochromocytoma cells, mouse pheochromocytoma cells, and by modeling SDH-deficiency using 3-nitropropionic acid (3-NPA).

Main Results:

• Mitochondrial ionophores showed preferential cytotoxicity towards SDHB-KO cells.
• Ym155 exhibited a potent, five-fold preferential cytotoxicity against SDHB-KO cells, validated across multiple cell types and models.
• Ym155-induced cytotoxicity was linked to SDH-deficiency-mediated DNA damage, impaired DNA repair, and enhanced ROS generation, independent of Survivin.

Conclusions:

• SDH-deficiency confers a unique susceptibility to Ym155, mediated by impaired DNA repair and increased ROS generation.
• The accumulation of succinate in SDH-deficient tumors inhibits KDM4 activity, contributing to DNA repair defects and Ym155 sensitivity.
• These findings reveal intrinsic susceptibilities of SDHB-deficient cancers that can be therapeutically leveraged.