New research has found that expression of AXL, a member of the TAM family of receptor tyrosine kinases, is correlated with poor outcomes in patients with HER2-positive breast cancer. AXL appears to mediate metastasis of the malignancy, and it could represent a promising therapeutic target.
“While some patients afflicted with HER2-positive breast cancer benefit from anti-HER2 therapeutic treatment, others may either be unresponsive or will develop resistance and relapse with metastatic disease,” wrote study authors led by Marie-Anne Goyette, a PhD candidate at the Montreal Clinical Research Institute in Canada. “Hence, defining the molecular mechanisms by which HER2 promotes cancer spreading may reveal novel anti-metastatic therapeutic strategies.” This study was published in Cell Reports.
First, the researchers established that AXL is expressed across a range of breast cancer subtypes, rather than just triple-negative disease as had been previously reported. They found that high expression of AXL correlates with adverse clinical outcomes when measured across breast cancer subtypes, and that high expression correlates with lung and brain metastases among those with HER2-positive disease.
They then used a mouse model to investigate the protein’s role in metastasis. They found that AXL appears to play a significant role in the development of metastases in HER2-positive disease, and this was independent of the AXL ligand Gas6. There is evidence that AXL and HER2 interact directly to form a physical complex at a cell’s surface. The interaction induces a transphosphorylation process that then promotes cell invasion, the authors wrote.
The metastatic process has a number of distinct steps involved. Again using the mouse model, the researchers showed that AXL is continuously required in HER2-positive cancer cells in order for efficient metastasis to take place, across those steps.
“Because our results support a role for AXL in promoting metastasis of HER2-positive breast cancer, we tested whether pharmacological inhibition of AXL might be a viable anti-metastatic treatment,” the authors wrote. They found that a small molecule inhibitor of AXL known as R428 decreased the number of circulating tumor cells, as well as the total lung metastatic burden in mice.
“We demonstrate a central role for AXL in promoting metastasis in the context of HER2-positive breast cancer,” they concluded. “Our data demonstrate that anti-AXL therapy is sufficient to reduce metastasis in HER2-positive cancers in experimental models.”