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Supplementary Figure 2 from Preclinical and Clinical Characterization of Fibroblast-derived Neuregulin-1 on Trastuzumab and Pertuzumab Activity in HER2-positive Breast Cancer

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posted on 2023-03-31, 22:45 authored by Cristina Guardia, Giampaolo Bianchini, Oriol Arpí-LLucià, Silvia Menendez, David Casadevall, Barbara Galbardi, Matteo Dugo, Sonia Servitja, Juan Carlos Montero, Luis Soria-Jiménez, MohammadA Sabbaghi, Raul Peña, Juan Madoz-Gúrpide, Belen Lloveras, Ana Lluch, Pilar Eroles, Joaquin Arribas, Atanasio Pandiella, Luca Gianni, Federico Rojo, Ana Rovira, Joan Albanell

Supplementary Figure 2 shows how NRG1/CAFs, but not normal mammary fibroblasts, mediate trastuzumab resistance in HER2-positive breast cancer cells.

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ISCIII

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ARTICLE ABSTRACT

To characterize expression of neuregulin-1 (NRG1), an HER3 ligand, in HER2-positive breast cancer and its relation with the efficacy of trastuzumab with or without pertuzumab. Characterization of NRG1 expression in tumor cell lines, in tumor specimens, and in cancer-associated fibroblasts (CAFs). Patient-derived CAFs were used to investigate NRG1 impact on the activity of trastuzumab with or without pertuzumab in HER2-positive breast cancer cells. The relationship between NRG1 expression and pathologic response to anti-HER2–based neoadjuvant therapy was assessed in a retrospective patient cohort and in the NeoSphere trial. NRG1 was expressed in HER2-positive breast cancer–derived fibroblasts at significantly higher levels than in cancer cells. NRG1 and the conditioned media (CM) from CAFs phosphorylated HER3 and AKT in cancer cells and mediated trastuzumab resistance. Stable genetic depletion of NRG1 from CAFs overcame trastuzumab resistance. Pertuzumab effectively suppressed trastuzumab resistance mediated by either NRG1 or CAF's CM. NRG1 engaged an epithelial-to-mesenchymal transition that was prevented by trastuzumab and pertuzumab. In clinical samples, stromal and/or tumor cell expression of NRG1 determined by immunohistochemistry was uncommon (13.2%) yet significantly linked with residual disease following trastuzumab-based neoadjuvant therapy. In the NeoSphere trial, the magnitude of the difference of pathologic complete response rates favoring the pertuzumab arm was higher in the NRG1-high group. CAF-derived NRG1 mediates trastuzumab resistance through HER3/AKT, which might be reverted by pertuzumab. In patients with HER2-positive breast cancer, high expression of NRG1 was associated to poor response to trastuzumab, but not in combination with pertuzumab.