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. Here, 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 ER+ 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 ECM-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.

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Journal
Cancer Research
Published
2026-02-18
DOI
https://doi.org/10.1158/0008-5472.can-25-3490
Primary Topic
Microbial metabolism and enzyme function
Type
article
Field-Weighted Citation Impact
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article

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

Yanbo Liu, Hazel M. Quinn, Athina Stravodimou, Harriet Kemp et al.
Cancer Research
Microbial metabolism and enzyme function
article

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

Yanbo Liu, Hazel M. Quinn, Athina Stravodimou, Harriet Kemp, Flavia Hughes, Anya A Nicholas, Rachel Brough, Rebecca Marlow, Carlos Ronchi, Beatrice A. Howard, Shozeb M Haider, Cathrin Brisken, Wolfgang Jarolimek, Marjan Iravani, Samuel Jouny, Clare M. Isacke, Laura Battista, Sarah Becker, Lara Perryman, Theodoros I. Roumeliotis, Renée L. Flaherty, Christopher J. Lord, William Yang, Maryse Fiche, Yueyun Zhang, Solene Pezot, Amelie Ziehme, Victoria Sanz-Moreno, N. C. Turner, K. Zaman, Harveena Padda, George Sflomos, Jyoti S. Choudhary, Giovanna Ambrosini, Alicia FC. Okines
article en

Abstract

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. Here, 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 ER+ 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 ECM-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.

Cancer Research
Synlab Czech (Czechia) (CZ), Royal Marsden NHS Foundation Trust (GB), Institute of Cancer Research (GB), The Francis Crick Institute (GB), Prevention Institute (US), Centre Hospitalier Universitaire Vaudois (CH), Institute of Cancer Research (CA), Formation Continue UNIL-EPFL (CH), AstraZeneca (Singapore) (SG), CRUK Lung Cancer Centre of Excellence (GB), Swiss Group For Clinical Cancer Research (CH), École Polytechnique Fédérale de Lausanne (CH), University of Brighton (GB), University of Lausanne (CH)
Good health and well-being
Openalex Percentile: Top 52%
Microbial metabolism and enzyme function
DOISourceOpenAlex
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