LOX Inhibition Creates a Synthetic lethal Therapeutic Opportunity in Breast Cancer 

Lysyl oxidase (LOX) is a secreted copper amine-oxidase that catalyses the cross-linking of collagen and elastin, to increase the strength and structural integrity of biological fibres. LOX is upregulated in some cancers, where it is associated with stiffening of the extracellular matrix (ECM) and activation of cell signals that increases proliferation and invasion, and thereby drive tumour progression. How the cross-linked ECM regulates intracellular signalling is still poorly understood, but we recently reported that LOX potentiates epidermal growth factor receptor (EGFR) signalling through activation of a secreted protease called HTRA1, which degrades TGFβ1, suppresses SMAD signalling and stimulates production of another secreted protein called matrilin2 (MATN2). MATN2 traps EGFR at the cell surface and presents it to EGF for efficient high fidelity activation.

We have developed a genetically engineered mouse model (GEMM) in which we floxed the Lox allele to allow us to selectively delete LOX specific mouse tissues. LOX depletion in mammary epithelial cells delays tumour initiation in a spontaneous model of breast cancer, and notably the tumours that do develop present a significant increase in the proportion of resident fibroblasts. Intriguingly, although these fibroblasts do not secrete LOX, they do upregulate the production of extracellular proteins. Moreover, in these tumours both the proliferation of the fibroblasts and the proliferation of the tumour cells is dependent on FGF1/FGFR1 signalling, creating a synthetic lethality that can be exploited for therapeutic gain. Our data suggest that we have discovered an inducible synthetic lethality that could provide therapeutic options for breast cancer patients.