Brain Metastases Resistant to Targeted Therapy Due to Gene Overexpression

A novel mechanism responsible for brain metastasis resistance to targeted therapy has been identified, which may help guide treatment strategies, according to a study published in Science Translational Medicine (2017;9[391]:eaal4682).

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Therapies designed to target genetic mutations that drive tumor growth have significantly improved prognoses in many patients with cancer. However, targeted therapies have not been as successful in controlling brain metastases resulting from breast cancer. Metastases from brain cancer are driven by an overexpression of the human epidermal growth factor 2 (HER2) gene. Previous research has attributed targeted drugs ineffectiveness to their inability to penetrate the blood-brain barrier, but further research is needed to support this belief.

Rakesh K Jain, PhD, director of Steele Laboratories of Tumor Biology, MGH Radiation Oncology Department, Massachusetts General Hospital (Boston, MA), and colleagues conducted a study to examine the microenvironment of brains with metastases. Researchers confirmed in mouse models that cells from HER2-positive breast cancers become resistant to anti-HER2 treatment when implanted in the brain but not in other tissues.

After confirming this relationship, researchers further confirmed that human epidermal growth factor 3 (HER3)—part of the same signaling pathway that includes HER2—is overexpressed in brain metastases of HER2-positive breast cancers from both mice and patient samples. In an effort to slow the growth of brain metastases, researchers reported that neither a HER3-targeting drug nor one that interferes with the interaction between HER2 and HER3 were effective. However, combined therapy with an anti-HER2 plus an anti-HER3 drug significantly slowed tumor growth.

“HER3 has been associated with treatment resistance in several types of cancer, and our findings indicate that the overexpression of HER3 within the microenvironment of brain metastases reprograms the signaling pathways shut down by HER2 suppression,” commented Gino B Ferraro, PhD, Steel Laboratories, in a press release (May 24, 2017).

Authors of the study assert that their findings will impact targeted therapy administration in the near future. Clinical trials to assess HER2 and HER3 targeting drugs in combination for the treatment of brain metastases are needed.—Zachary Bessette