Overcoming Therapy Resistance: AXL as a Novel KLF4 Target in Melanoma Treatment

What is it about?

Malignant melanoma (“black skin cancer”) continues to pose a significant clinical challenge due to its pronounced adaptability. Although targeted and immune-therapies have significantly improved treatment possibilities in the last decade, there is still room for improvement in both approaches, as many patients continue to experience treatment resistance. In our recent study published in the journal Neoplasia, we identified the receptor tyrosine kinase AXL- an important protein molecule promoting therapy resistance, tumor aggressiveness and metastasis- as a key effector of the MEK5/ERK5/KLF4 signaling pathway , which is activated during targeted therapy for melanoma and contributes to the development of resistance. We were able to show that AXL is significantly upregulated during treatment with MEK inhibitors, which are routinely used in targeted therapy regimes. This induction can be blocked by pharmacological and genetic inhibition of ERK5 or its transcriptional effector KLF4, thereby effectively limiting the migratory capacity and invasiveness of melanoma cells. In addition, we demonstrate that in metastatic melanoma cell lines characterized by high AXL levels combined treatment with MEK and ERK5 inhibitors and KLF4 depletion significantly reduced AXL expression and tumor cell invasiveness.

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Why is it important?

Our findings expand the current understanding of how melanoma cells respond to targeted therapy and develop drug resistance. As high AXL expression is a frequent characteristic of both targeted and immune therapy resistant metastatic melanoma the identification of AXL as a target of the druggable ERK5/KLF4 signaling cascade opens up new therapeutic perspectives.

Perspectives