Blocking interplay between TERT and c-Myc: a new therapeutic strategy for BRAFV600E/pTERT double mutated tumors.

Tumors with coexisting mutations of BRAF^V600E and TERT promoter (pTERT) 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 BRAF transcription, and TERT interacted with and stabilized c-Myc. Meanwhile, we verified that c-Myc transcriptionally repressed PP2Ac, 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 BRAF^V600E/pTERT 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 BRAF^V600E/pTERT double mutated cancer cells both in vitro and vivo, with good biosafety. These findings suggest that blocking the interaction between TERT and c-Myc may be a promising therapeutic option for BRAF^V600E/pTERT double mutated tumors.