Mutación del gen BRAF V600E en el cáncer papilar de tiroides y su efecto en la terapia con yodo radiactivo ( 131 I) posquirúrgica: ¿deberíamos modificar nuestra estrategia terapéutica?

Ayala, Maite Domínguez; Rodríguez, Amaia Expósito; González, Amaia Bilbao; Gabiña, Pablo Mínguez; Rodríguez, Teresa Gutiérrez; Zarate, Emilia Rodeño Ortiz de; Carrillo, Maitane García; Treviño, Borja Barrios

doi:10.1016/j.ciresp.2018.02.018

Cited by 4 publications

(1 citation statement)

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“…Brose et al has recently reported that Vemurafenib showed antitumour activity in patients with progressive, BRAFV600E-positive papillary thyroid cancer refractory to radioactive iodine who had never been treated with a multikinase inhibitor [ 15 ]. The mutation of the BRAFV600E gene is related with greater resistance to postoperative treatment with 131I since the onset of the disease [ 16 ]. A new study suggests that the PLX4032 may be effective in the 25 to 50% of patients with papillary thyroid cancer who develop resistance to radioactive iodine, a standard treatment.…”

Section: Introductionmentioning

confidence: 99%

Synergistic inhibition of MEK/ERK and BRAF V600E with PD98059 and PLX4032 induces sodium/iodide symporter (NIS) expression and radioiodine uptake in BRAF mutated papillary thyroid cancer cells

Zhang

Chen

2018

Thyroid Res

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Background and AimsThe activating mutation BRAFV600E is a frequent genetic event in papillary thyroid carcinomas (PTC). Mutation BRAFV600E is associated with the loss of a sodium/iodine symporter (NIS), and subsequent radioiodide-refractory (RAI) metastatic disease. Use of BRAF V600E inhibitors could partly restore NIS expression and Iodide uptake by inhibition of mitogen-activated protein kinase (MAPK) pathway. Previous study has reported that the BRAF V600E inhibitors could re-activate MAPK signals. In the present study, we investigated whether the combination treatment of BRAF V600E inhibitor and MAPK signal inhibitor could more effectively increase NIS expression and RAI uptake, and explore the mechanisms.MethodsBCPAP and K1 cells were exposed to increasing concentrations of BRAF V600E inhibitor PLX4032 (0.01 μM, 0.1 μM, 1 μM) or MEK/ERK inhibitor PD98059 (0.01 μM, 0.1 μM, 1 μM) or with their association or/and in the presence of 3 mM perchlorate (ClO− 4) for 0–72 h. Iodide uptake and expression of BRAF, phosphorylated (p) ERK1/2, NIS were detected.ResultsPLX4032 or PD98059 alone did not induce NIS expression and increase Iodide uptake in BCPAP and K1 cells. But combined treatment of PLX4032 and PD98059 significantly induce NIS expression and increase Iodide uptake in BCPAP and K1 cells. PLX4032 alone inhibited p-ERK expression at early time, and re-activated p-ERK expression at late time. However, combined treatment of PLX4032 and PD98059 completely inhibited p-ERK expression.ConclusionSimultaneously suppressing BRAF V600E and p-ERK restored NIS expression and increase Iodide uptake in PTC cells, which was associated the inhibition of p-ERK expression. The results warrants clinical trials to confirm.

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Section: Introductionmentioning

confidence: 99%