Research On The Resistance Mechanism Of Melanoma Treatment

Activating BRAF (V600E) kinase mutation occurs in over half of melanomas. Recent clinical studies have demonstrated that PLX4032, a potent and selective inhibitor of mutant BRAF, exhibits a remarkable activity in patients with mutant BRAF melanomas. However, acquired drug resistance invariably develops after the initial treatment. Identification of acquired resistance mechanisms may inform the development of new therapies that elicit long term responses of melanomas to BRAF inhibitors.Here we report that increased expression of AEBP1(adipocyte enhancer-binding protein1) confers acquired resistance to BRAF inhibition in melanoma. AEBP1is shown to be highly upregulated in PLX4032-resistant melanoma cells due to the hyper activation of PI3K/Akt-CREB signaling pathway. This upregulated AEBP1expression thus leads to the activation of NF-kB via accelerating IkBa degradation. In addition, inhibition of PI3K/Akt-CREB-AEBP1-NF-B pathway greatly reverses the PLX4032-resistant phenotype of melanoma cells. Furthermore, increased expression of AEBP1is also validated in post-relapsed tumors in two of four patients with acquired resistance to PLX4032. Therefore, these results reveal a novel PI3K/Akt-CREB-AEBP1-NF-kB pathway whose activation contributes to acquired resistance to BRAF inhibition, and suggests that this pathway, particularly AEBP1, may represent a novel therapeutic target for treating BRAF inhibitor-resistant melanoma.The tumor suppressor p53can be activated in the case of cellular stressis, aim to protect cell by initating the DNA repair mechanism or to remove the irreversible damaged cells by induced apoptosis, as to preserve the malignant transformation. This gene encoding p53is leading to the loss of function by widely mutated in tumor tissues, But in human melanoma the p53is wild type and the expression level is high.It is in the opposite of the malignant nature of this disease.Means the p53has lost the effectively tumor suppressor function in human melanoma.. Here we showed that the p53protein level was stabled and rised under the ER stress, the p53were gathered in the nuclear. On the function, the p53was selectively activated by ER stress, and selectively transcriptional up-regulated the GPCl,the host gene of microRNA149*, to increased the expression of microRNA149*. The up-regulation of microRNA149*mediated by p53is necessary for melanoma to adapt to ER stress, and inhibited the expression of p53or microRNA149*remarkable undermine the resistence of melanoma to ER stress.