ABSTRACT
Intrinsic and acquired resistance to mitogen-activated protein kinase inhibitors (MAPKi) in melanoma remains a major therapeutic challenge. Here, we show that the clinical development of resistance to MAPKi is associated with reduced tumor expression of the melanoma suppressor Autophagy and Beclin 1 Regulator 1 (AMBRA1) and that lower expression levels of AMBRA1 predict a poor response to MAPKi treatment. Functional analyses show that loss of AMBRA1 induces phenotype switching and orchestrates an extracellular signal-regulated kinase (ERK)-independent resistance mechanism by activating focal adhesion kinase 1 (FAK1). In both in vitro and in vivo settings, melanomas with low AMBRA1 expression exhibit intrinsic resistance to MAPKi therapy but higher sensitivity to FAK1 inhibition. Finally, we show that the rapid development of resistance in initially MAPKi-sensitive melanomas can be attributed to preexisting subclones characterized by low AMBRA1 expression and that cotreatment with MAPKi and FAK1 inhibitors (FAKi) effectively prevents the development of resistance in these tumors. In summary, our findings underscore the value of AMBRA1 expression for predicting melanoma response to MAPKi and supporting the therapeutic efficacy of FAKi to overcome MAPKi-induced resistance.
Subject(s)
Adaptor Proteins, Signal Transducing , Drug Resistance, Neoplasm , Melanoma , Protein Kinase Inhibitors , Melanoma/drug therapy , Melanoma/genetics , Melanoma/metabolism , Humans , Drug Resistance, Neoplasm/drug effects , Drug Resistance, Neoplasm/genetics , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Adaptor Proteins, Signal Transducing/metabolism , Adaptor Proteins, Signal Transducing/genetics , Cell Line, Tumor , Animals , Mice , Focal Adhesion Kinase 1/metabolism , Focal Adhesion Kinase 1/antagonists & inhibitors , Xenograft Model Antitumor Assays , Mitogen-Activated Protein Kinases/metabolism , Gene Expression Regulation, Neoplastic/drug effects , FemaleABSTRACT
The Society for Melanoma Research (SMR) was created 20 years ago and has unequivocally contributed to the vast progress of the field, particularly for the treatment of melanoma patients with metastatic disease by facilitating synergistic collaborations between clinicians, researchers at the bench, and industry. In commemoration of the 20th anniversary of the first SMR International Congress (held in 2003 in Philadelphia), we look to the future by highlighting the perspectives of the next generation of rising stars, medical, and graduate students across six continents.
