Therapeutic targeting of FOS in mutant cancers through removing TERT suppression of apoptosis via regulating and .

The telomerase reverse transcriptase (TERT) has long been pursued as a direct therapeutic target in human cancer, which is currently hindered by the lack of effective specific inhibitors of TERT. The FOS/GABPB/(mutant) cascade plays a critical role in the regulation of mutant , in which FOS acts as a transcriptional factor for to up-regulate the expression of GABPB, which in turn activates mutant but not wild-type promoter, driving TERT-promoted oncogenesis. In the present study, we demonstrated that inhibiting this cascade by targeting FOS using FOS inhibitor T-5224 suppressed mutant cancer cells and tumors by inducing robust cell apoptosis; these did not occur in wild-type cells and tumors. Mechanistically, among 35 apoptotic cascade-related proteins tested, the apoptosis induced in this process specifically involved the transcriptional activation of tumor necrosis factor-related apoptosis-inducing ligand receptor 2 () and inactivation of two key players in the apoptotic cascade, which normally initiate and suppress the apoptotic cascade, respectively. These findings with suppression of FOS were reproduced by direct knockdown of TERT and prevented by prior knockdown of TRAIL-R2. Further experiments demonstrated that TERT acted as a direct transcriptional factor of up-regulating its expression. Thus, this study identifies a therapeutic strategy for promoter mutation-driven cancers by targeting FOS in the FOS/GABPB/(mutant) cascade, circumventing the current challenge in pharmacologically directly targeting TERT itself. This study also uncovers a mechanism through which TERT controls cell apoptosis by transcriptionally regulating two key players in the apoptotic cascade.