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Abstract
Background: The past 30 years have seen little improvement in the survival of patients with stage IV melanoma. Following the discovery of activating BRAF mutations in most melanomas, a wealth of preclinical experimentation has validated the BRAF/MAPK pathway as an excellent therapeutic target in melanoma. Despite these encouraging results, early clinical trials on BRAF/MAPK inhibition have been disappointing. Objective: In the current review, we discuss how differences between the preclinical and clinical settings may influence the response of melanoma cells to BRAF/MEK inhibition. As the BRAF/MEK signaling pathway is not solely responsible for the growth and survival of melanoma cells, we further discuss the therapeutic utility of inhibiting the PI3K/AKT and mTOR pathways both alone and in combination with BRAF/MEK. Conclusion: In looking ahead to the future, it is likely that new advances in melanoma biology, such as the identification of melanoma stem cells and a greater understanding of intratumoral heterogeneity, may play a role in the design of any future melanoma targeted therapy.
Acknowledgements
The authors received grant support from the American Cancer Society Institutional Research Grant #93-032-13 and the Melanoma Research Foundation.