Abstract PD4-07: Targeting latent residual HER2+ breast cancer brain metastatic cells

Abstract Approximately fifty percent of breast cancer patients with brain metastasis are positive for human epidermal growth factor receptor 2 (HER2+). Systemically effective cytotoxic drugs, and HER2 targeted therapies are ineffective on brain metastases. Current understanding of HER2 brain metastatic disease is limited as biopsying brain metastatic lesions and detecting micro-metastasis from asymptomatic patients with residual disease remains a challenge. Therefore, to isolate disseminated tumor cells that stay latent in the brain, while retaining their metastasis-initiating capabilities, we performed a phenotypic screen in mouse employing human breast cancer cell lines. Using this approach, we isolated isogenic latent residual cells (Lat) and metachronous brain metastatic outbreaks (M-BM). Phenotypically stable latent cells display stem cell-like characteristics, downregulate immune activating sensors and survive in equilibrium with innate immune surveillance, while M-BM escape and metastasize. Brain-tropic Lat and M-BM cells are resistant to HER2 targeted therapies - lapatinib, neratinib and tucatinib. Transcriptomic analysis identified AXL, a receptor tyrosine kinase from the TAM receptor family, to be highly enriched in brain-tropic Lat and M-BM. Moreover, AXL is over expressed in metachronous brain metastasis samples compared to matched primary tumors from HER2+ breast cancer patients. AXL activation and overexpression has been associated with chemoresitance mechanisms, dormancy maintenance, invasion, tumor angiogenesis, immune regulation, metastasis and poor prognosis in cancer patients. Therefore, we hypothesized AXL promotes residual/latent breast cancer survival and brain metastatic relapse in HER2+ breast cancer. shRNA depletion of AXL in Lat and M-BM resulted in reduced oncosphere formation, an assay used to measure tumor or metastasis initiating capacity. Brain metastatic incidence was significantly attenuated in mice bearing AXL depleted M-BM compared to their controls. Bemcentinib, an AXL inhibitor currently in clinical trials for non-small cell lung cancer, triple negative breast cancer, pancreatic cancer and melanoma, alone or in combination with lapatinib, neratinib or tucatinib, reduced oncosphere formation in HER2 therapy resistant Lat and M-BM cells. Ongoing experiments are designed to assess the impact of bemcentinib on brain metastasis in vivo and to mechanistically define how AXL promotes survival of latent residual and brain metastatic HER2+ breast cancer cells. Citation Format: Mauricio Marquez-Palencia, Srinivas Malladi. Targeting latent residual HER2+ breast cancer brain metastatic cells [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD4-07.