LOX Inhibition Disrupts a Collagen-Integrin-MYC Axis to Suppress Progression of Invasive Lobular Carcinoma

Invasive lobular carcinoma (ILC) accounts for 15% of breast cancers yet lacks specific therapy because ILCs are underrepresented in clinical trials and preclinical models are lacking. In this study, we established intraductal xenograft models to test whether the clinical pan-lysyl-oxidase inhibitor PXS-5505, now in phase I/IIa trials for myelofibrosis, can exploit the collagen-rich matrix dependency in ILC created by CDH1 loss. PXS-5505 remodeled fibrillar collagen and halted tumor expansion and metastatic seeding across estrogen receptor-positive and triple-negative models without systemic toxicity. Genome-wide CRISPR screens revealed ITGAV and ITGB5 as synthetic lethal partners of CDH1, and LOX inhibition downregulated their expression, together with MYC, NF-κB, and AP-1 transcriptional programs. Collagen fiber density/alignment and MYC/AP-1 gene signatures served as pharmacodynamic readouts of drug activity. These data uncover a tractable extracellular matrix-integrin-MYC axis in ILC and nominate PXS-5505, alone or with endocrine therapy, for window-of-opportunity trials in this understudied breast cancer subtype. Significance: A clinical stage LOX inhibitor slows tumor progression and alters multiple molecular endpoints in invasive lobular carcinoma, providing a translatable therapeutic strategy for this frequent breast cancer subtype currently lacking specific therapies.