AMBRA1 levels predict resistance to MAPK inhibitors in melanoma

Intrinsic and acquired resistance to mitogen - activated protein kinase\r\ninhibitors (MAPKi) in melanoma remains a major therapeutic challenge.\r\nHere, we show that the clinical development of resistance to MAPKi is\r\nassociated with reduced tumor expression of the melanoma suppressor\r\nAutophagy and Beclin 1 Regulator 1 (AMBRA1) and that lower expression\r\nlevels of AMBRA1 predict a poor response to MAPKi treatment. Functional\r\nanalyses show that loss of AMBRA1 induces phenotype switching and\r\norchestrates an extracellular signal - regulated kinase (ERK) -\r\nindependent resistance mechanism by activating focal adhesion kinase 1\r\n(FAK1). In both in vitro and in vivo settings, melanomas with low AMBRA1\r\nexpression exhibit intrinsic resistance to MAPKi therapy but higher\r\nsensitivity to FAK1 inhibition. Finally, we show that the rapid\r\ndevelopment of resistance in initially MAPKi - sensitive melanomas can\r\nbe attributed to preexisting subclones characterized by low AMBRA1\r\nexpression and that cotreatment with MAPKi and FAK1 inhibitors (FAKi)\r\neffectively prevents the development of resistance in these tumors. In\r\nsummary, our findings underscore the value of AMBRA1 expression for\r\npredicting melanoma response to MAPKi and supporting the therapeutic\r\nefficacy of FAKi to overcome MAPKi - induced resistance.