Abstract
The BRAF V600E mutation is commonly observed in papillary thyroid cancer (PTC) and predominantly activates the MAPK pathway. Presence of BRAF V600E predicts increasing risk of recurrence and higher mortality rate, and treatment options for such patients are limited. Vemurafenib, a BRAF V600E inhibitor, is initially effective, but cells inevitably develop alternative mechanisms of pathway activation. Mechanisms of primary resistance have been described in short-term cultures of PTC cells; however, mechanisms of acquired resistance have not. In the present study, we investigated possible adaptive mechanisms of BRAF V600E inhibitor resistance in KTC1 thyroid cancer cells following long-term vemurafenib exposure. We found that a subpopulation of KTC1 cells acquired resistance to vemurafenib following 5 months of treatment with the inhibitor. Resistance coincided with the spontaneous acquisition of a KRAS G12D activating mutation. Increases in activated AKT, ERK1/2, and EGFR were observed in these cells. In addition, the resistant cells were less sensitive to combinations of vemurafenib and MEK1 inhibitor or AKT inhibitor. These results support the KRAS G12D mutation as a genetic mechanism of spontaneously acquired secondary BRAF inhibitor resistance in BRAF V600E thyroid cancer cells.
Highlights
The majority of patients with papillary thyroid cancer (PTC) have excellent long-term outcomes with standard therapy, up to approximately 25% have a more aggressive course, presenting with or developing distant metastases
Western blot analysis showed that the antiproliferative effect of vemurafenib on KTC1 cells was associated with the inhibition of both ERK1/2 and AKT phosphorylation (Figure 1B, 1C), which are downstream of BRAF and PI3K, respectively
Most patients diagnosed with PTC have excellent long-term outcomes after primary surgical therapy, the presence of an oncogenic BRAF V600E mutation is associated with refractory disease and worse clinical outcomes
Summary
The majority of patients with papillary thyroid cancer (PTC) have excellent long-term outcomes with standard therapy, up to approximately 25% have a more aggressive course, presenting with or developing distant metastases. The mutation constitutively activates the catalytic activity of the BRAF kinase, a member of the RAF family of serine/threonine enzymes. This activity leads to activation of MEK and ERK1/2 kinases and results in functional dependence of the cells upon the BRAF/MEK/ERK cascade for growth and survival. The selective BRAF V600E inhibitors vemurafenib and dabrafenib have shown promise in clinical trials [8,9,10]. These results are quite favorable, as with all kinase inhibitors, resistance develops. Research has recently focused on elucidating possible mechanisms of resistance to BRAF V600E inhibitors
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