Figure 6.

Hypothesized effect of mitogen‐activated protein kinase kinase (MEK) and autophagy inhibition on growth, survival and invasion of melanoma. (a) In normal growth conditions, activating BRAF mutations increase extracellular signal‐regulated kinase (ERK) signalling to inhibit adenosine monophosphate‐activated protein kinase (AMPK) and maintain autophagic activity (Autoph.) within survival limits. (b) MEK inhibitors (MEKi) de‐represses AMPK and allows autophagy to increase above the upper survival threshold (*) leading to activation of apoptosis or growth arrest. Subsequent activation of adaptive prosurvival signalling, such as CD271, contributes to drug resistance by lowering autophagic activity below the threshold for apoptosis, allowing reactivation of cell growth, proliferation and invasion. (c) Treatment of drug‐resistant melanoma with specific autophagy inhibitors, such as PIK‐III, reduces prosurvival autophagic activity below the lower survival threshold (#) leading to accumulation of cytotoxic by‐products and activation of apoptosis.