Tumor Suppressor Merlin Offers a New Therapeutic Strategy for HER2-Low Breast Cancer

Abstract

HER2 (human epidermal growth factor receptor 2) receptor is a membrane tyrosine kinase and when activated affects cell proliferation and survival. HER2 amplification is the primary pathway of HER2 overexpression and is a major driver of tumor development and progression in the subset of BCs. Currently there is an ongoing clinical revolution in the expanded use of HER2 directed therapies to include HER2-low patients. Greater than 60% of BCs are HER2-low. The tumor suppressor protein Merlin suppresses mitogenesis by blocking receptor tyrosine kinase signaling and arrests migration/invasion. It has been suggested that merlin interacts with mitochondria. We hypothesize that HER2-low BC cells, under the loss of functional Merlin due to oxidative stress causing mitochondrial fission by PINK1, will elevate HER2 signaling. This could dramatically alter HER2-low cell sensitivity to anti-HER2 directed therapy. When oxidative stress was applied to HER2+ cells, an increased level of phosphorylated HER2 (Y877) was found in the EVs. This connection of Merlin with mitochondrial remodeling constitutes a new source of strategies for preferentially increasing the sensitivity of HER2-low BC to HER2 directed therapies and provides a new molecular targeting axis for a large previously untreated cohort of BC patients.