AXL-WRNIP1 Mediated Replication Stress Response Promotes Therapy Resistance and Metachronous Metastasis in HER2+ Breast Cancer

Abstract

Therapy resistance and metastatic progression are primary causes of cancer-related mortality. Disseminated tumor cells possess adaptive traits that enable them to reprogram their metabolism, maintain stemness, and resist cell death, facilitating their persistence to drive recurrence. The survival of disseminated tumor cells also depends on their ability to modulate replication stress in response to therapy while colonizing inhospitable microenvironments. In this study, we discovered that nuclear translocation of AXL, a TAM receptor tyrosine kinase, and its interaction with WRNIP1, a DNA replication stress response factor, promotes the survival of HER2 targeted therapy-resistant breast cancer cells in the brain. Using preclinical models, we demonstrated that knocking down or pharmacologically inhibiting AXL or WRNIP1 increased replication stress and attenuated metastatic latency and relapse. Our findings suggest that targeting the replication stress response, which is a shared adaptive mechanism in therapy-resistant and metastasis-initiating cells, could reduce metachronous metastasis and enhance the response to standard-of-care therapies