ArticleProceedings of the National Academy of Sciences of the United States of America2024
AMBRA1 levels predict resistance to MAPK inhibitors in melanoma.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed.
- Article
- A critical role of FAK signaling in Rac1-driven melanoma cell resistance to MAPK pathway inhibition.Oncogene · 2025Article
- Transcriptome-wide decoding the roles of aberrant splicing in melanoma MAPK-targeted resistance evolution.EMBO reports · 2025Article
- Rab40 GTPases regulate AMBRA1-mediated transcription and cell migration.Journal of cell science · 2025Article
- A Paradoxical AKT: Exploring the Promise and Challenges of PI3K/AKT/mTOR Targeted Therapies.Journal of cancer immunology · 2024Article
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21 authors.
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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.
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Registered trials
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