CRM1 and BRAF inhibition synergize and induce tumor regression in BRAF mutant melanoma
Menée in vitro et à l'aide de xénogreffes, cette étude suggère l'intérêt d'un traitement combinant un inhibiteur de CRM1 et un inhibiteur de BRAF pour les patients atteints d'un mélanome présentant une mutation du gène BRAF
Resistance to BRAF inhibitor therapy places priority on developing BRAF inhibitor-based combinations that will overcome de novo resistance and prevent the emergence of acquired mechanisms of resistance. The CRM1 receptor mediates the nuclear export of critical proteins required for melanoma proliferation, survival and drug resistance. We hypothesize that by inhibiting CRM1-mediated nuclear export, we will alter the function of these proteins resulting in decreased melanoma viability and enhanced BRAF inhibitor anti-tumoral effects. To test our hypothesis, selective inhibitors of nuclear export (SINE) analogs KPT-185, KPT-251, KPT-276 and KPT-330 were used to induce CRM1 inhibition. Analogs PLX4720 and PLX4032 were used as BRAF inhibitors. Compounds were tested in xenograft and in-vitro melanoma models. In vitro, we found CRM1 inhibition decreases melanoma cell proliferation independent of BRAF mutation status and synergistically enhances the effects of BRAF inhibition on BRAF-mutant melanoma by promoting cell cycle arrest and apoptosis. In melanoma xenograft models, CRM1 inhibition reduces tumor growth independent of BRAF or NRAS status and induces complete regression of BRAF V600E tumors when combined with BRAF inhibition. Mechanistic studies show that CRM1 inhibition was associated with p53 stabilization, and pRb and Survivin modulation. Furthermore we found that BRAF inhibition abrogates ERK phosphorylation associated with CRM1 inhibition, which may contribute to the synergy of the combination. In conclusion, CRM1 inhibition impairs melanoma survival in both BRAF mutant and WT melanoma. The combination of CRM1 and BRAF inhibition synergizes and induces melanoma regression in BRAF mutant melanoma.
http://mct.aacrjournals.org/content/early/2013/04/24/1535-7163.MCT-12-1171.abstract