Repurposing statins in combination therapy for effective ablation of metastatic breast cancer

Metastatic breast cancer (mBC) remains an incurable disease with limited treatment options, highlighting the need for novel therapeutic approaches. The eventual development of resistance to commonly used regimens leading to relapse suggested the presence of intrinsically resistant heterogeneous cell populations. Our previous work identified heterogeneous metastatic tumor cell populations with distinct molecular characteristics driven by MACC1 (Metastasis Associated Colon Cancer 1), which is a key driver of metastasis and therapeutic resistance in multiple solid cancers, including breast cancer. We demonstrated that lovastatin (transcriptional inhibitor of MACC1) treatment ablated the metastatic cells through Macc1 downregulation. Building on this foundation, we evaluated the efficacy of lovastatin in lung metastases and elucidated its regulatory pathways in mBC. Spatial transcriptomics on an Indian breast cancer patient cohort revealed heterogeneous MACC1 expression across tumors, which correlated with aggressive clinical features. Heterogeneous tumor cells [bulk tumor (Bulk), primary tumor (T1), lung-specific metastatic (L1) cells] were characterized from a metastatic murine model, with L1 showing the highest proliferation rate and MACC1 expression. Lovastatin treatment significantly downregulated MACC1 expression in L1 cells resulting in inhibition of key metastatic phenotypes like proliferation and migration, as well as altered cell type-specific gene expression of programmes like EMT and dormancy, with protein–ligand docking simulations with Sp1, indicating a potential transcriptional regulatory mechanism. Finally, we explored the therapeutic efficacy of lovastatin in combination with chemotherapy and demonstrated that lovastatin effectively ablated chemoresistant tumor cells in mBC. The translational implications of this research could identify patient subgroups that may benefit from statin–chemotherapy combinations and support the repurposing of statins as cost- effective adjuvant therapies for mBC.