The T-Box Transcription Factors TBX2 and TBX3 Are Molecular Targets of Piroctone Olamine in the Treatment of Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) has a poor 5-year survival rate of < 10% and its incidences are continuously rising worldwide. This highlights an urgent need for effective therapies to reduce its burden. Repurposing commercially available non-cancer drugs that inhibit key drivers of PDAC may facilitate the rapid identification of effective drugs. In PDAC, the expression of the TBX2 and TBX3 transcription factors correlates with metastasis and poor patient survival. This study showed that when TBX3 was depleted in 2D and 3D PDAC cell culture models, the cells underwent senescence and had reduced proliferative ability and spheroid growth. Interestingly, TBX2 levels increased in shTBX3 cells and depleting TBX2 in these cells inhibited their migration. Our results thus demonstrated that TBX2 and TBX3 have distinct oncogenic functions and that any effective anti-PDAC drug must inhibit them both. The antifungal piroctone olamine, previously identified as a TBX2-/3-targeting drug in melanoma and rhabdomyosarcoma, inhibited the levels of TBX2 and TBX3 and recapitulated the phenotypes observed when they were knocked down in 2D and 3D PDAC cell culture models. Impressively, piroctone olamine was also effective in PDAC patient-derived organoids. Together, our data demonstrate the potential of piroctone olamine to be repurposed for treating TBX2-/3-dependent PDAC.