A Mount Sinai School of Medicine and Case Western Reserve University team has found a new use for the dopamine receptor antagonist trifluoperazine: restoring the sensitivity of tumors to epidermal growth factor receptor inhibitors.1 The key is trifluoperazine's off-target activity related to the export of the tumor suppressor forkhead box O1, which suggests other drugs in the class also could be repurposed to treat resistant cancers.
Although epidermal growth factor receptor (EGFR) inhibitors are a mainstay for treating lung cancers, the drugs are limited by primary or acquired drug resistance that can arise through multiple molecular mechanisms.2-4
To better understand the mediators of that resistance, the Sinai-Case Western group focused on two tumor suppressors: Kruppel-like factor 6 (KLF6; COPEB; ZF9) and forkhead box O1 (FOXO1). Prior studies showed that KLF6 levels are lower in lung adenocarcinomas than in matched normal lung tissue.
FOXO1 is the direct transcriptional activator of KLF6