Abstract IA8: BRAF and MEK resistance in melanoma

Abstract

Abstract The melanoma field has had a long history of frustrating experiences in clinical trials. Most of these were in immunotherapy, although all approaches in biotherapy, chemotherapy and radiation therapy have been similarly unsuccessful for the past 30 years with unchanged five-year survival rates of 15% for advanced disease. The therapy arena is dramatically changing with a new generation of BRAF inhibitors. Particularly those with high specificity for the mutant kinase are effective in killing cells carrying the BRAFV600E mutation. Two BRAF inhibitors have increased progression-free survival and overall survival from the disease. Considering the poor success rate from previous trials, the currently accumulated data are dramatic and exciting. However, there are no cures and all treated patients recur due to the development of resistance. In treated melanoma cells with BRAFV600E there are no new mutations, except the appearances of splice variants and mutations in NRAS in some tumors. Instead, cells learn to signal around inhibited BRAF through CRAF or ARAF to activate MEK and ERK. At the same time compensatory signaling activates receptor tyrosine kinases such as IGFR1 and PDGFR, leading to activation of the PI3K pathway. Potentially, additional pathways can be activated likely requiring an individual assessment of the mechanisms of resistance. Inhibition of the newly activated pathways can prevent progression in experimental systems but has not yet been validated in patients. In contrast to inhibitors of BRAF, inhibitors for MEK appear to induce mutations in either MEK 1 or MEK 2. It is not yet clear whether the mutations occur at multiple or unique sites. Likely, similar mutational events as in MEK will occur when inhibitors of ERK are given to cells over prolonged time periods. In summary, the MAPK pathway has emerged as a major driver for melanoma cells. However, when the malignant cells are treated with inhibitors for BRAF/MEK/ERK they develop secondary resistance. Why do some cells survive the drug insult? This question is particularly pertinent for inhibitors of mutant BRAF because all cells invariably contain the mutations. The reasons for this intrinsic or primary resistance are not clear and will require a major investigational effort in future years. Experimental studies in immunodeficient mice have shown that single melanoma cells are sufficient to induce a tumor, thus, the goal has to be the elimination of all cells and not just the majority of cells. Strategies to achieve this goal will in part depend on the mechanisms of survival of a sub-population of malignant cells. It is most likely that non-genetic events are responsible for the survival and they will be discussed.