Blocking interplay between TERT and c-Myc: a new therapeutic strategy for BRAF^V600E/pTERT double mutated tumors

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Coexisting BRAF V600E and TERT promoter (pTERT) mutations are linked to aggressive tumors and poor survival.
• Effective treatments for these double-mutated tumors are limited, and their underlying regulatory mechanisms are poorly understood.

Purpose of the Study:

• To elucidate the mutual regulatory mechanism between BRAF and TERT in double-mutated tumors.
• To develop a novel therapeutic strategy targeting the TERT-c-Myc interaction.

Main Methods:

• Investigated the interaction between BRAF, TERT, and c-Myc using molecular biology techniques.
• Assessed the role of c-Myc in regulating BRAF transcription and PP2Ac expression.
• Designed and synthesized peptide-conjugated aurous nanoparticles (AuNP-p-CPS62 and AuNP-CPS62) to disrupt TERT-c-Myc binding.
• Evaluated the efficacy of nanoparticles in suppressing tumor cell growth in vitro and in vivo.

Main Results:

• Demonstrated that BRAF and TERT mutually regulate each other, with c-Myc playing a central role.
• Established that c-Myc promotes BRAF transcription and is stabilized by TERT interaction.
• Showed that c-Myc represses PP2Ac, leading to c-Myc stabilization and promoting tumor progression.
• Confirmed that AuNP-p-CPS62 and AuNP-CPS62 effectively inhibit the growth of BRAF V600E/pTERT double-mutated cancer cells with good biosafety.

Conclusions:

• A positive regulatory network involving BRAF, TERT, c-Myc, and PP2A drives the progression of BRAF V600E/pTERT double-mutated tumors.
• Disrupting the TERT-c-Myc interaction using peptide-conjugated nanoparticles represents a promising therapeutic approach for these aggressive cancers.