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Lookup NU author(s): Professor Penny Lovat
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).
© 2024 the Author(s). 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.
Author(s): Leo LD, Pagliuca C, Kishk A, Rizza S, Tsiavou C, Pecorari C, Dahl C, Pacheco MP, Tholstrup R, Brewer JR, Berico P, Hernando E, Cecconi F, Ballotti R, Bertolotto C, Filomeni G, Gjerstorff MF, Sauter T, Lovat P, Guldberg P, De Zio D
Publication type: Article
Publication status: Published
Journal: Proceedings of the National Academy of Sciences of the United States of America
Year: 2024
Volume: 121
Issue: 25
Online publication date: 13/06/2024
Acceptance date: 20/05/2024
Date deposited: 05/02/2025
ISSN (print): 0027-8424
ISSN (electronic): 1091-6490
Publisher: National Academy of Sciences
URL: https://doi.org/10.1073/pnas.2400566121
DOI: 10.1073/pnas.2400566121
Data Access Statement: The transcriptomic datasets analyzed in the current study are public available under the GEO numbers GSE50509, GSE65185, GSE129127, and GSE116237. The RNAseq datasets from the TCGA-SKCM are available at http://cancergenome.nih.gov/. The protein data from the CCLE melanoma cell lines are available at portals.broadinstitute.org/ccle
PubMed id: 38870061
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