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Updated: Jun 24, 2025
Assessment of Resistance to Tyrosine Kinase Inhibitors by an Interrogation of Signal Transduction Pathways by Antibody Arrays
Published on: September 19, 2018
AMBRA1 levels predict resistance to MAPK inhibitors in melanoma
Luca Di Leo1, Chiara Pagliuca1, Ali Kishk2
1Melanoma Research Team, Center for Autophagy, Recycling and Disease, Danish Cancer Institute, Copenhagen 2100, Denmark.
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.
Insights
Reduced Autophagy and Beclin 1 Regulator 1 (AMBRA1) in melanoma predicts poor response to mitogen-activated protein kinase inhibitors (MAPKi). Loss of AMBRA1 activates focal adhesion kinase 1 (FAK1), driving resistance. Combination therapy with MAPKi and FAKi overcomes resistance.
Area of Science:
- Oncology
- Melanoma Research
- Molecular Biology
Background:
- Melanoma resistance to mitogen-activated protein kinase inhibitors (MAPKi) is a significant clinical hurdle.
- Autophagy and Beclin 1 Regulator 1 (AMBRA1) acts as a melanoma suppressor, but its role in MAPKi resistance is unclear.
Purpose of the Study:
- To investigate the association between AMBRA1 expression and MAPKi resistance in melanoma.
- To elucidate the mechanisms underlying AMBRA1-mediated resistance.
- To evaluate the therapeutic potential of targeting AMBRA1 or its downstream pathways.
Main Methods:
- Analysis of AMBRA1 expression in melanoma tumors from patients treated with MAPKi.
- In vitro and in vivo functional studies using melanoma cell lines and xenograft models.
- Assessment of resistance mechanisms involving focal adhesion kinase 1 (FAK1) and extracellular signal-regulated kinase (ERK) pathways.
- Evaluation of combination therapy with MAPKi and FAK1 inhibitors (FAKi).
Main Results:
- Reduced tumor expression of AMBRA1 correlates with clinical resistance to MAPKi and predicts poor treatment response.
- Loss of AMBRA1 promotes phenotype switching and induces MAPKi resistance via an ERK-independent FAK1 activation pathway.
- Melanomas with low AMBRA1 exhibit intrinsic MAPKi resistance but are sensitive to FAKi.
- Cotreatment with MAPKi and FAKi effectively prevents resistance development in preclinical models.
Conclusions:
- AMBRA1 expression serves as a predictive biomarker for melanoma response to MAPKi therapy.
- Targeting FAK1 in combination with MAPKi is a promising strategy to overcome or prevent MAPKi resistance in melanoma.
- Understanding the role of AMBRA1 in melanoma progression and drug resistance opens new therapeutic avenues.
