TERT promoter mutation determines apoptotic and therapeutic responses of BRAF-mutant cancers to BRAF and MEK inhibitors: Achilles Heel

• Published in: Proceedings of the National Academy of Sciences - PNAS 2020-07, Vol.117 (27), p.15846-15851
• Main Authors: Tan, Jie, Liu, Rengyun, Zhu, Guangwu, Umbricht, Christopher B., Xing, Mingzhao
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Apoptosis - drug effects; Biological Sciences; Cancer; Cell culture; Cell Death; Cell Line, Tumor; Colon; Colon cancer; Colonic Neoplasms; Drug resistance; Drug Resistance, Neoplasm - drug effects; Female; Humans; Imidazoles - pharmacology; Inhibitors; Kinases; MAP kinase; MEK inhibitors; Melanoma; Melanoma - genetics; Mice, Nude; Mitogen-Activated Protein Kinases - metabolism; Mutants; Mutation; Oximes - pharmacology; Promoter Regions, Genetic - drug effects; Promoter Regions, Genetic - genetics; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins B-raf - drug effects; Proto-Oncogene Proteins B-raf - genetics; Pyridones - pharmacology; Pyrimidinones - pharmacology; Telomerase - genetics; Therapeutic targets; Thyroid; Thyroid cancer; Thyroid Neoplasms - genetics; Tumors; Xenograft Model Antitumor Assays
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2004707117

Combination use of BRAF V600E inhibitor dabrafenib and MEK inhibitor trametinib has become a standard treatment for human cancers harboring BRAF V600E. Its anticancer efficacies vary, however, with dramatic efficacy in some patients and drug resistance/ tumor recurrence in others, which is poorly understood. Using thyroid cancer, melanoma, and colon cancer cell models, we showed that dabrafenib and trametinib induced robust apoptosis of cancer cells harboring both BRAF V600E and TERT promoter mutations but had little proapoptotic effect in cells harboring only BRAF V600E. Correspondingly, the inhibitors nearly completely abolished the growth of in vivo tumors harboring both mutations but had little effect on tumors harboring only BRAF V600E. Upon drug withdrawal, tumors harboring both mutations remained hardly measurable but tumors harboring only BRAF V600E regrew rapidly. BRAF V600E/MAP kinase pathway is known to robustly activate mutant promoter of TERT, a strong apoptosis suppressor. Thus, for survival, cancer cells harboring both mutations may have evolved to rely on BRAF V600E-promoted and high-TERT expression-mediated suppression of apoptosis. As such, inhibition of BRAF/MEK can trigger strong apoptosis-induced cell death and hence tumor abolishment. This does not happen in cells harboring only BRAF V600E as they have not developed reliance on TERT-mediated suppression of apoptosis due to the lack of mutant promoter-driven high-TERT expression. TERT promoter mutation governs BRAF-mutant cancer cells’ apoptotic and hence therapeutic responses to BRAF/MEK inhibitors. Thus, the genetic duet of BRAF V600E and TERT promoter mutation represents an Achilles Heel for effective therapeutic targeting and response prediction in cancer.