Inhibition of the endosomal recycling pathway downregulates HER2 activation and overcomes resistance to tyrosine kinase inhibitors in HER2-positive breast cancer

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dc.contributor.authorMishra, Anurag
dc.contributor.authorHourigan, David
dc.contributor.authorLindsay, Andrew J.
dc.contributor.funderUniversity College Corken
dc.date.accessioned2022-09-16T08:47:24Z
dc.date.available2022-09-16T08:47:24Z
dc.date.issued2022-01-11
dc.date.updated2022-09-14T14:04:21Z
dc.description.abstractThe development of HER2-targeted therapies has led to a dramatic improvement in outcomes for breast cancer patients. However, nearly all patients with metastatic HER2-positive breast cancer will eventually progress on these therapies due to innate or acquired resistance. Recent evidence suggests that the endosomal recycling of HER2 plays an important role in regulating its oncogenic signalling. Here we report that the expression of Rab coupling protein (RCP), a key regulator of endosomal recycling, positively correlates with that of HER2 and HER3 in breast tumours, and high RCP expression is predictive of poor relapse-free and overall survival in patients with HER2-amplified breast cancer. Chemical and genetic inhibition of endosomal recycling leads to a reduction in the total cellular levels of HER2 and HER3 and inhibits the activation of their downstream signalling pathways. We find that HER2 and HER3 that have been internalised from the plasma membrane are diverted to lysosomes for degradation when endosomal recycling is blocked. Primaquine (PQ), a small molecule inhibitor of the endosomal recycling pathway, synergises with HER2-targeting tyrosine kinase inhibitors and overcomes innate and acquired resistance to these TKIs. Moreover, TKI-induced drug tolerant persister cells are vulnerable to endosomal recycling inhibitors. These findings suggest that inhibition of endosomal recycling represents a promising therapeutic strategy for treating drug resistant HER2-positive breast cancer.en
dc.description.statusPeer revieweden
dc.description.versionPublished Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationMishra, A., Hourigan, D. and Lindsay, A. J. (2022) 'Inhibition of the endosomal recycling pathway downregulates HER2 activation and overcomes resistance to tyrosine kinase inhibitors in HER2-positive breast cancer', Cancer Letters, 529, pp. 153-167. doi: 10.1016/j.canlet.2022.01.003en
dc.identifier.doi10.1016/j.canlet.2022.01.003en
dc.identifier.eissn1872-7980
dc.identifier.endpage167en
dc.identifier.issn0304-3835
dc.identifier.journaltitleCancer Lettersen
dc.identifier.startpage153en
dc.identifier.urihttps://hdl.handle.net/10468/13612
dc.identifier.volume529en
dc.language.isoenen
dc.publisherElsevier B.V.en
dc.rights© 2022, the Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)en
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en
dc.subjectEndosomal recycling pathwayen
dc.subjectHER2-targeted therapiesen
dc.subjectDrug synergyen
dc.subjectDrug resistanceen
dc.subjectPrimaquineen
dc.titleInhibition of the endosomal recycling pathway downregulates HER2 activation and overcomes resistance to tyrosine kinase inhibitors in HER2-positive breast canceren
dc.typeArticle (peer-reviewed)en
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