Signaling Pathway Modulates Melanoma Response to Autophagy Inhibitors

Scientists identified a new link between autophagy and a key melanoma signaling pathway, in which changes in signaling may affect treatment response, according to a study published in Cancer Research.

Autophagy is a metabolic process that allows cancer cells to survive under stressful conditions of the tumor microenvironment, and affects treatment response to drugs targeting melanoma. This challenge has sparked several studies examining autophagy inhibitors as a potential strategy.

“We have already shown that Wnt5A, a component of the Wnt pathway, plays critical roles in melanoma progression,” said corresponding author Ashani Weeraratna, PhD. “Our new study indicates a link between the Wnt pathway and autophagy, whereby Wnt is a key player in the response to autophagy inhibitors and likely affects the efficacy of this class of drugs.”

Wnt5A is a key molecule in the Wnt signaling pathway that correlates with melanoma progression. To assess the interplay between Wnt5A and autophagy, investigators combined expression studies in human melanoma biopsies with function analyses in mouse models and cell lines.

The findings showed a direct correlation between levels of Wnt5A and activation of autophagy. Furthermore, they discovered a reciprocal regulation of autophagy and Wnt signaling.

The investigators examined the affect Wnt signaling activation had on the response of melanoma to an autophagy inhibitor in vitro and in vivo.

They found that cells with high levels of Wnt5A and autophagy activation were less sensitive and needed higher concentrations of the inhibitor. Additionally, the pharmacological modulation of the β-catenin molecule of the Wnt pathway significantly improved the response of aggressive melanoma cells to autophagy inhibition. As a result, it lowered the dose needed to eradicate the cells.

“By dissecting the crosstalk between the autophagy pathway and the Wnt pathway, we discovered that signaling changes that occur within the tumor may affect the response to autophagy inhibitors,” said first author Abibatou Ndoye. “Our observations will be helpful to determine which patients will be more response to this therapeutic strategy and how we can target the pathways that affect the response, in order to overcome resistance.”

Based on the study findings, the authors noted that autophagy inhibitors could play another role in the treatment of melanoma that goes beyond increasing the cells’ sensitivity to treatment.