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

Area of Science:

• Oncology
• Cancer Biology
• Biochemistry

Background:

• Invasive lobular carcinoma (ILC) represents 15% of breast cancers but lacks targeted therapies due to underrepresentation in trials and limited preclinical models.
• CDH1 loss in ILC creates a dependency on a collagen-rich extracellular matrix (ECM).

Purpose of the Study:

• To evaluate the efficacy of the pan-lysyl-oxidase inhibitor PXS-5505 in preclinical models of ILC.
• To investigate the mechanism by which PXS-5505 affects the tumor microenvironment and identify potential biomarkers of response.

Main Methods:

• Establishment of intraductal xenograft models for ILC.
• Treatment with PXS-5505 and assessment of tumor expansion and metastatic seeding.
• Genome-wide CRISPR screens to identify synthetic lethal partners of CDH1.
• Analysis of ECM remodeling, gene expression (MYC, NF-κB, AP-1), and integrin expression (ITGAV, ITGB5).

Main Results:

• PXS-5505 remodeled fibrillar collagen, halting tumor expansion and metastatic seeding in both ER+ and triple-negative ILC models.
• No systemic toxicity was observed with PXS-5505 treatment.
• CRISPR screens identified ITGAV and ITGB5 as synthetic lethal partners of CDH1.
• LOX inhibition downregulated ITGAV, ITGB5, MYC, NF-κB, and AP-1.
• Collagen fiber density/alignment and MYC/AP-1 gene signatures served as pharmacodynamic readouts.

Conclusions:

• A tractable ECM-integrin-MYC axis in ILC was uncovered.
• PXS-5505 demonstrates potential as a therapeutic agent for ILC, warranting further investigation.
• PXS-5505 may be suitable for window of opportunity trials, alone or in combination with endocrine therapy.