Issues

To determine how melanomas that have adapted and become addicted to MAPK inhibitors (MAPKi) respond to MAPKi withdrawal, Hong, Moriceau, and colleagues characterized the phenotypes of MAPKi-resistant melanoma cell lines after drug withdrawal. MAPKi-resistant cell lines exhibited either a cell death–predominant drug addiction phenotype characterized by ERK hyperactivation and DNA damage, or a slow cycling–predominant drug addiction phenotype. DNA damage–induced PARP1-dependent cell death was essential for the cell death–predominant phenotype, and DNA damage repair inhibitors such as PARPi induced apoptosis in cell death–predominant melanoma cell lines and caused slow cycling–predominant melanoma cell lines to switch to a cell death–predominant phenotype. Combined PARPi and vemurafenib treatment induced MAPKi-addicted tumor regression after MAPKi withdrawal. These findings identify a therapeutically exploitable mechanism driving MAPKi addiction in melanoma. For details, please see the article by Hong, Moriceau, and colleagues on page 74.