A sensitive and diploid T ALL cell line MOLT16, and a polyploid and resistant

However, the responses are not long lasting and result in progressive disease in ma jority of patients. Significant progress has been made in understanding the mechanisms of the intrinsic and ac quired resistance that can be both MEK dependent and MEK independent. To overcome MEK dependent resist ance the combination of a BRAF inhibitor with a MEK inhibitor, KU-0063794 構造 has resulted in sig nificant extension of PFS, when compared to dabrafenib as single agent. BRIM 7 trial combining vemurafenib with a potent inhibitor of MEK1 2 demonstrated a high response rate in mel anoma patients na ve to BRAF inhibitors. However, adding the MEK inhibitor to vemurafenib progressive patients, has led to a much less impressive response rate, The well documented immunotherapy approaches for melanoma targeting key T cells immune check points such as CTLA 4 and PD1 PD L1 have already validated the merits for combining these agents with targeted therapy approaches.<br>br<> Targeted therapy increases the sensitivity of the tumor for immunotherapy by recruiting immune cells into melanoma lesions supporting the merit of combining those two types of therapy to achieve clinical benefits. Other pos sible approaches to overcome developing resistance Lenalidomide 構造 are to target other aspects of melanoma biology downstream of BRAF such as cell cycle regulation, tumor metabolism or activation of an immune response. Potential therapeutic strategies include the use of CDK4 inhibitors such as PD 0332991, and inhibitors of glycolytic regulators of tumor metabolism such as inhibitors of pyruvate dehydrogenase kinase or lactate dehydrogenase that inhibit tumor cell glu cose metabolism.<br>br<> A cancer drug based on oncolytic virus has also succeeded in a late stage clinical trial giving an other agent for multi modality care. In conclusion, many mechanisms of resistance have been driving progression during anti BRAF purchase LY294002 therapy, likely in volve MAP kinase pathway in most cases, and it is likely that more than one resistant mechanism is present at the same time. Its difficult, if not impossible, to target all the resistance mechanisms after they have been activated, but combination therapy used upfront may prevent resistance, Combination therapy approaches that incorporate targeted agents and immunotherapy are most promising and are already clinically explored.<br>br<> Des pite the remaining challenges, it is certain that rational combination therapy for treatment of patients resistant to BRAF inhibitors represents the future of metastatic mel anoma treatment. Novel concepts Melanoma is a complex and heterogeneous disease and tumor may be composed of distinct cell populations with distinct molecular features and varying response to treatment. Inter and intra tumor heterogeneity within primary tumours and between primary and metastatic sites as well as developing resistance suggest the need for novel approaches to identify predictive markers closer to patients tumor allowing for rational design of combination therapies instead of using a single biopsy assumption. Additional challenge is how to use the knowledge that cancer development and progression de pends on immune system and stroma and several areas of new investigations provide promissing insights with regard to development of successful treatments.