HER-3 surface expression increases in advanced colorectal cancer representing a potential therapeutic target

Emily Capone; Thordur Tryggvason; Ilaria Cela; Beatrice Dufrusine; Morena Pinti; Francesco Del Pizzo; Helga Sigrun Gunnarsdottir; Tommaso Grottola; Vincenzo De Laurenzi; Stefano Iacobelli; Rossano Lattanzio; Gianluca Sala

doi:10.1038/s41420-023-01692-8

HER-3 surface expression increases in advanced colorectal cancer representing a potential therapeutic target

Cell Death Discov. 2023 Oct 28;9(1):400. doi: 10.1038/s41420-023-01692-8.

Authors

Emily Capone^{1

2}, Thordur Tryggvason³, Ilaria Cela^{1

2}, Beatrice Dufrusine^{2

4}, Morena Pinti⁵, Francesco Del Pizzo², Helga Sigrun Gunnarsdottir³, Tommaso Grottola⁶, Vincenzo De Laurenzi^{1

2}, Stefano Iacobelli⁷, Rossano Lattanzio^{1

2}, Gianluca Sala^{8

9}

Affiliations

¹ Department of Innovative Technologies in Medicine & Dentistry, University "Gabriele d'Annunzio" of Chieti-Pescara, Chieti, Italy.
² Center for Advanced Studies and Technology (CAST), University "Gabriele d'Annunzio" of Chieti-Pescara, Chieti, Italy.
³ Department of Pathology, Landspítali - The National University Hospital of Iceland, Reykjavik, Iceland.
⁴ Department of Bioscience and Technology for Food, Agriculture and Environment, University of Teramo, Teramo, Italy.
⁵ Department of Medical, Oral and Biotechnological Sciences, University "Gabriele d'Annunzio" of Chieti-Pescara, Chieti, Italy.
⁶ Surgical Oncology Unit, Casa di Cura Pierangeli, 65124, Pescara, Italy.
⁷ MediaPharma s.r.l., Via Colonnetta 50/A, Chieti, Italy.
⁸ Department of Innovative Technologies in Medicine & Dentistry, University "Gabriele d'Annunzio" of Chieti-Pescara, Chieti, Italy. [email protected].
⁹ Center for Advanced Studies and Technology (CAST), University "Gabriele d'Annunzio" of Chieti-Pescara, Chieti, Italy. [email protected].

Abstract

HER-3 (also known as ErbB-3) is a human epidermal growth factor receptor tyrosine kinases family member, and its expression in CRC (colorectal cancer) tissues was previously associated with poor prognosis. In this study, HER-3 expression was analyzed by immunohistochemistry in two cohorts of early and advanced metastatic CRC patients. The first cohort included 180 patients diagnosed with CRC in absence of lymph nodes or distant metastases (Stage I and Stage II), while the second was obtained from 53 advanced metastatic CRC patients who developed synchronous (SM) and metachronous (MM) liver metastases. In the first early-stage CRC cohort, 86 out of 180 (47.8%) tumors showed membranous expression of HER-3, with a mean percentage of positive tumor cells of 25.7%; conversely, in advanced metastatic CRC primary tumors, HER-3 was detected in all specimens, with a mean percentage of positive tumor cells of 76.1%. Kaplan-Meier curves showed that in the advanced metastatic CRC group, patients with HER-3^high tumors had a significantly lower Cancer-Specific Survival (CSS) rate compared to patients with HER-3^low tumors (p = 0.021). Importantly, this worse CSS rate was observed only in the MM subgroup of patients with HER-3^high tumors (p = 0.002). Multivariate analysis confirmed that high HER-3 expression represents a significant and strong risk factor for death in patients developing MM liver metastases (Hazard Ratio = 64.9; 95% Confidence Interval, 4.7-886.6; p = 0.002). In addition, using a specific anti-HER-3 antibody-drug conjugate, named EV20/MMAF, we showed that HER-3 + CRC cells can be efficiently targeted in vitro and in vivo. Overall, this study confirms that surface HER-3 is highly expressed in CRC and reveals that HER-3 expression increases in metastatic CRC patients compared to early stage. Importantly, the results suggest that HER-3 has a prognostic and therapeutic value in patients developing MM liver metastases.