Strategic trastuzumab mediated crosslinking driving concomitant HER2 and HER3 endocytosis and degradation in breast cancer

Wymant, Jennifer Mary, Sayers, Edward John ORCID: https://orcid.org/0000-0002-2621-1119, Muir, Duncan and Jones, Arwyn Tomos ORCID: https://orcid.org/0000-0003-2781-8905 2020. Strategic trastuzumab mediated crosslinking driving concomitant HER2 and HER3 endocytosis and degradation in breast cancer. Journal of Cancer 11 (11) , pp. 3288-3302. 10.7150/jca.32470

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Abstract

Efficacious anticancer therapies for targeting plasma membrane receptors with antibody based therapeutics are often contingent on sufficient endocytic delivery of receptor and conjugate to lysosomes. This results in downregulation of receptor activity and, in the case of antibody-drug conjugates (ADCs), intracellular release of a drug payload. The oncogenic receptor HER2 is a priority therapeutic target in breast cancer. Known as an “endocytosis resistant” receptor, HER2 thwarts the receptor downregulating efficiency of the frontline treatment trastuzumab and reduces the potential of trastuzumab-based therapies such as trastuzumab-emtansine. We previously demonstrated that strategically inducing trastuzumab and HER2 crosslinking in breast cancer cells promoted endocytosis and lysosomal delivery of the HER2-trastuzumab complex, stimulating downregulation of the receptor. Here we reveal that HER3, but not EGFR, is also concomitantly downregulated with HER2 after crosslinking. This is accompanied by strong activation of MEK/ERK pathway that we show does not directly contribute to HER2/trastuzumab endocytosis. We show that crosslinking induced trastuzumab endocytosis occurs via clathrin-dependent and independent pathways and is an actin-dependent process. Detailed ultrastructural studies of the plasma membrane highlight crosslinking-specific remodelling of microvilli and induction of extensive ruffling. Investigations in a cell model of acquired trastuzumab resistance demonstrate, for the first time, that they are refractory to crosslinking induced HER2 endocytosis and downregulation. This implicates further arrest of HER2 internalisation in developing trastuzumab resistance. Overall our findings highlight the potential of receptor crosslinking as a therapeutic strategy for cancer while exposing the ability of cancer cells to develop resistance via endocytic mechanisms.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Earth and Environmental Sciences Pharmacy
Uncontrolled Keywords:	HER2, crosslinking, endocytosis
Publisher:	Ivyspring International Publisher
ISSN:	1837-9664
Funders:	Wellcome Trust
Date of First Compliant Deposit:	22 April 2020
Date of Acceptance:	4 January 2020
Last Modified:	25 May 2024 10:25
URI:	https://orca.cardiff.ac.uk/id/eprint/131173

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