University of Oulu

Tiia J Honkanen, Milla E K Luukkainen & Jussi P Koivunen (2023) Role of human epidermal growth factor receptor 3 in treatment resistance of anaplastic lymphoma kinase translocated non-small cell lung cancer, Cancer Biology & Therapy, 24:1, DOI: 10.1080/15384047.2023.2256906

Role of human epidermal growth factor receptor 3 in treatment resistance of anaplastic lymphoma kinase translocated non-small cell lung cancer

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Author: Honkanen, Tiia J.1,2,3; Luukkainen, Milla E. K.1,2,3; Koivunen, Jussi P.1,2,3
Organizations: 1Department of Oncology and Radiotherapy, Oulu University Hospital, Oulu, Finland
2Medical Research Center Oulu, Oulu, Finland
3Cancer and Translational Medicine Research Unit, University of Oulu, Oulu, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 5.3 MB)
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Language: English
Published: Informa, 2023
Publish Date: 2023-10-11


Background: ALK tyrosine kinase inhibitors (TKI) have revolutionized the treatment of ALK+ non-small cell lung cancer (NSCLC), and therapy resistance occurs in virtually all patients. Multiple TKI resistance mechanisms have been characterized, including ERBB receptor coactivation. In this study, we investigated the role of HER3 in ALK TKI resistance.

Methods: In vitro studies were carried out using ALK+ NSCLC cell lines H3122, H2228, and DFCI032. Pharmacological co-targeting of ALK and HER3 was investigated with ALK and ERBB TKIs, and HER3 knockdown was achieved using the CRISPR-Cas9 system. Co-localization of ALK and HER3 was investigated by immunoprecipitation (IP) and proximity ligation assay (PLA) in vitro and in vivo using six ALK+ NSCLC tumor samples.

Results: In all tested cell lines, combined targeting with ALK and pan-ERBB TKI resulted in marked inhibition of colony formation and long-term (72 h) downregulation of pAKT levels. HER3 knockdown resulted in multiple effects on ALK+ cell lines, including the downregulation of ALK expression and visible morphological changes (H2228). Co-immunoprecipitation (IP) and proximation ligation assay (PLA) experiments provided evidence that both ALK and HER3 could interact in vitro, and this finding was verified by PLA using ALK+ NSCLC tumors.

Conclusions: This study provides evidence that HER3 may mediate TKI resistance in ALK+ NSCLC. Interestingly, we were able to show that both translocated ALK and HER3 could interact. Joint targeting of ALK and HER3 could be further investigate in ALK+ NSCLC.

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Series: Cancer biology & therapy
ISSN: 1538-4047
ISSN-E: 1555-8576
ISSN-L: 1538-4047
Volume: 24
Issue: 1
Article number: 2256906
DOI: 10.1080/15384047.2023.2256906
Type of Publication: A1 Journal article – refereed
Field of Science: 3122 Cancers
Funding: This work was supported by the University of Oulu, Oulu University Hospital, and Finnish Cancer Institute.
Copyright information: © 2023 The Author(s). Published with license by Taylor & Francis Group, LLC. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.