The BRAFᵀ¹⁷⁹⁹ᴬ mutation confers sensitivity of thyroid cancer cells to the BRAFⱽ⁶⁰⁰ᴱ inhibitor PLX4032 (RG7204)
2011
Xing, Joanna | Liu, Ruixin | Xing, Mingzhao | Trink, Barry
Aberrant signaling of the Ras-Raf-MEK-ERK (MAP kinase) pathway driven by the mutant kinase BRAFⱽ⁶⁰⁰ᴱ, as a result of the BRAFᵀ¹⁷⁹⁹ᴬ mutation, plays a fundamental role in thyroid tumorigenesis. This study investigated the therapeutic potential of a BRAFⱽ⁶⁰⁰ᴱ-selective inhibitor, PLX4032 (RG7204), for thyroid cancer by examining its effects on the MAP kinase signaling and proliferation of 10 thyroid cancer cell lines with wild-type BRAF or BRAFᵀ¹⁷⁹⁹ᴬ mutation. We found that PLX4032 could effectively inhibit the MAP kinase signaling, as reflected by the suppression of ERK phosphorylation, in cells harboring the BRAFᵀ¹⁷⁹⁹ᴬ mutation. PLX4032 also showed a potent and BRAF mutation-selective inhibition of cell proliferation in a concentration-dependent manner. PLX4032 displayed low IC₅₀ values (0.115–1.156μM) in BRAFⱽ⁶⁰⁰ᴱ mutant cells, in contrast with wild-type BRAF cells that showed resistance to the inhibitor with high IC₅₀ values (56.674–1349.788μM). Interestingly, cells with Ras mutations were also sensitive to PLX4032, albeit moderately. Thus, this study has confirmed that the BRAFᵀ¹⁷⁹⁹ᴬ mutation confers cancer cells sensitivity to PLX4032 and demonstrated its specific potential as an effective and BRAFᵀ¹⁷⁹⁹ᴬ mutation-selective therapeutic agent for thyroid cancer.
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