Therapeutic targeting of FOS in mutant TERT cancers through removing TERT suppression of apoptosis via regulating survivin and TRAIL-R2

Significance Given that oncogenic hotspot mutations in the promoter of the gene for telomerase reverse transcriptase (TERT) are common, it has been attractive to develop therapeutic strategies targeting TERT in mutant TERT human cancers. No direct TERT inhibitor is currently available, however, hindering this pursuit. By targeting FOS in the FOS/GABPB/(mutant) TERT cascade using a FOS inhibitor to inhibit mutant TERT cancer cells and tumors through induction of apoptosis by relieving TERT suppression, this study identifies a therapeutic strategy of targeting the TERT cascade for cancers. This study also uncovers a molecular mechanism in which TERT controls apoptosis by specifically regulating two key players among many in the apoptotic cascade, answering a long-time question of how TERT suppresses apoptosis.