ALDH2 inhibition induces synthetic lethality in APC-deficient colorectal cancer via ROS/ASK1/JNK pathway

The mutation rate of adenomatous polyposis coli (APC) in colorectal cancer (CRC) reaches over 60%. However, how to use synthetic lethal strategies to screen and inhibit APC partners in CRC treatment still needs to be studied. We used bioinformatics methods to screen for potential synthetic lethal effects between aldehyde dehydrogenase 2 (ALDH2) and APC. Compared with wild-type APC cell lines, significantly reduced cell proliferation was detected after treatment of APC -deficient CRC cell lines with ALDH2 inhibitor (disulfiram). Flow cytometry analysis revealed that disulfiram treatment caused G0/G1 phase arrest and increased apoptosis in APC -deficient CRC cell lines. The levels of reactive oxygen species (ROS) were elevated in APC- deficient CRC cell lines. Treatment of APC -deficient CRC cell lines with disulfiram further induced the continuous accumulation of ROS, which activates the ASK1/JNK pathway, ultimately triggering apoptosis. Disulfiram treatment significantly inhibited tumor cell proliferation, increased apoptosis, and diminished the tumor growth rate of APC mutation tumors in xenograft models. Taken together, our results indicate that ALDH2 inhibition can effectively target APC -deficient CRC cells by increasing ROS levels, activating ASK1 and JNK pathways, and inducing synthetic lethality. These findings indicate that ALDH2 inhibition represents a promising therapeutic strategy for overcoming APC -deficient CRC.