Target genes in HER2 preclinical mammary carcinoma models and therapeutic vaccines

About 20% of breast cancer patients overexpress HER2. HER2 targeted therapies have revolutionized HER2-positive breast cancer treatment; however, a significant proportion of patients present resistance to the therapy. One of the causes of resistance to HER2 targeted therapy is the loss of HER2 expression in metastases or recurrences. In the Laboratory of Immunology and Biology of Metastasis directed by Prof. Pier-Luigi Lollini, a model for cancer heterogeneity and HER2 loss has been developed, consisting of three murine cell lines (MamBo) and their clones, characterized by different expression patterns of HER2 linked to different phenotypical features and aggressiveness. The transcriptomic analysis of MamBo cell lines enlightened an altered cholesterol regulation, particularly in the sense of HER2 loss and it was compared with the transcriptome of patients with a similar clinical condition. In both models, the HER2 loss was associated with higher expression of genes involved in cholesterol-rich signaling and intracellular transport. Pharmacological strategies, commonly used to menage cholesterolemia, were tested in vitro on MamBo cell lines to counteract HER2 loss and cancer progression. Statin exerted a cytostatic effect, especially on the HER2 loss cell line model. To harness this cytostatic activity, it was combined with senescence inducing compounds, such as transcriptional inhibitors, or with anti-HER2 targeted therapy. In both the combinatorial approaches, statin enhanced drug efficacy. A prototype virus-like particle (VLP)-based vaccine against HER2 showed promising therapeutic activity in human HER2 transgenic mouse models without eradicating 100% of tumors. To improve VLP-HER2 therapeutic efficacy, a combined approach with another VLP-based vaccine against proprotein convertase subtilisin/kexin type 9 (PCSK9) was evaluated. This combinatorial approach inhibited tumor growth, prolonged tumor free survival in vivo and elicited antibodies that inhibited 3D tumor growth of human breast cancer cell lines, suggesting that targeting cholesterol transport in HER2-positive mammary carcinoma models can improve anti-HER2 immunological approaches.