There is a synthetic lethal interaction between the ARID1A and aldehyde dehydrogenase 2 (ALDH2) genes in cholangiocarcinoma, according to a new study published in Genes & Disease. This suggests that inhibiting ALDH2 pharmacologically could be a new strategy for treating ARID1A-deficient cholangiocarcinoma.

Synthetic lethality is a type of genetic interaction where the combination of 2 genetic events leads to cell death. This can be exploited to discover novel anticancer drug candidates.

In the present study, a team of researchers led by Li Guo, PhD, from Nanjing University of Posts and Telecommunications in China showed that cholangiocarcinoma cells deficient in ARID1A had higher levels of reactive oxygen species (ROS) compared to wild type cells (ARID1A is a protein that is responsible for maintaining genome stability). Moreover, inhibiting ALDH2 with disulfiram dramatically increased the accumulation of ROS.


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Higher intracellular ROS levels caused by ARID1A deficiency or disulfiram treatment alone could be tolerated by cells. However, when these 2 events combine, they would increase ROS levels inside cells so much that they can no longer tolerate it.

High levels of ROS directly cause DNA damage and activate the apoptosis signal-regulating kinase 1 signaling pathway. The DNA damage also induces apoptosis via the PARP-Caspase3 pathway, the authors explained, and said that these results validate that the ARID1A:ALDH2 interaction via ROS “strikes twice.”

They added that their results underscore the potential value of repurposing disulfiram as precision medicine in cholangiocarcinoma treatment.

Cholangiocarcinoma is a heterogeneous group of rare malignant tumors originating from cells of the biliary tree. Early clinical diagnosis markers and effective nonsurgical treatment options are lacking for the disease. Surgery is also not indicated in case of metastatic disease and mortality rates are still high, therefore, new and efficient treatment options are urgently needed.

Reference

Liang T, Jia L, Duan R, et al. Inhibition of ALDH2 by disulfiram leads to synthetic lethality via ROS strikes twice in ARID1A-deficient cholangiocarcinoma. Genes Dis. Published online March 16, 2022. doi:10.1016/j.gendis.2022.02.005