The important role of immune microenvironment in resistance to MAPK pathway-targeted therapy


Many studies focus on the mechanism of combination therapy against tumor drug resistance. However, a novel view that the resistance is related to immune system has been reported recently. Smith et al. demonstrated that the factors within immune microenvironment can promote the resistance to mitogen-activated protein kinase (MAPK) pathway-targeted therapy. The article was published on Cancer Discovery.


Up to 90% of melanomas have aberrant high expression level of RAF-MEK-ERK kinases, the components of MAPK signaling pathway. The therapy targeting this signaling pathway has been proved effective, however, the efficiency is limited due to the onset of drug resistance. Researchers found tumor necrosis factor-α (TNF-α) derived from macrophage act as an important melanoma growth factor that contributes to resistance against MAPK pathway inhibitors. The action is dependent on the melanocytic-specific microphthalmia transcription factor (MITF), a mediator of multiple survival and antiapoptotic genes. Importantly, MAPK inhibitors enable to increase the number of tumor-related macrophages, meanwhile elevate TNF-α and MITF expression levels, indicating an enhancement of resistance to MAPK inhibitors. Moreover, a treatment targeting melanoma cells as well as immune microenvironment, that inhibit TNF-α signaling by IκB kinase inhibitors, profoundly increase the efficiency of MAPK pathway inhibitors. All together, researchers showed the crucial role of immune microenvironment in generating resistance and provided a potential therapeutic strategy of melanoma. 


Cancer Discov. 2014 Oct;4(10):1214-29.


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