Blocking interplay between TERT and c-Myc: a new therapeutic strategy for double mutated tumors.

Tumors with coexisting mutations of and promoter () are more aggressive and associated with poor patient survival. However, the effective treatments for these tumors are limited, and the mutual regulation mechanism between these two molecules remains largely unclear. Here, we demonstrated that BRAF and TERT could mutually regulate each other, and c-Myc played a vital role in this process. Mechanistically, c-Myc could promote transcription and TERT interacted with and stabilized c-Myc. Meanwhile, we verified that c-Myc transcriptionally repressed , which, as the core catalytic subunit of PP2A, leads to dephosphorylation of c-Myc at Ser62, decreasing its stability. These molecular events promoted the progression of double mutated tumors by forming positive regulatory networks. To develop therapeutic strategy for this kind of tumors, we designed two peptides p-CPS62 and CPS62 to break the interaction between TERT and c-Myc, and constructed the corresponding aurous nanoparticles (AuNP-p-CPS62 and AuNP-CPS62). The results showed that AuNP-p-CPS62 and AuNP-CPS62, especially the former, effectively suppressed the growth of double mutated cancer cells both and , with good biosafety. These findings suggest that blocking the interaction between TERT and c-Myc may be a promising therapeutic option for double mutated tumors.