Stress-induced Rab11a-exosomes induce amphiregulin-mediated cetuximab resistance in colorectal cancer

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dc.citation.issue6
dc.citation.volume13
dc.contributor.authorMason JD
dc.contributor.authorMarks E
dc.contributor.authorFan S-J
dc.contributor.authorMcCormick K
dc.contributor.authorWilson C
dc.contributor.authorHarris AL
dc.contributor.authorHamdy FC
dc.contributor.authorCunningham C
dc.contributor.authorGoberdhan DCI
dc.date.accessioned2024-07-02T21:06:37Z
dc.date.available2024-07-02T21:06:37Z
dc.date.issued2024-06-18
dc.description.abstractExosomes are secreted vesicles made intracellularly in the endosomal system. We have previously shown that exosomes are not only made in late endosomes, but also in recycling endosomes marked by the monomeric G-protein Rab11a. These vesicles, termed Rab11a-exosomes, are preferentially secreted under nutrient stress from several cancer cell types, including HCT116 colorectal cancer (CRC) cells. HCT116 Rab11a-exosomes have particularly potent signalling activities, some mediated by the epidermal growth factor receptor (EGFR) ligand, amphiregulin (AREG). Mutant activating forms of KRAS, a downstream target of EGFR, are often found in advanced CRC. When absent, monoclonal antibodies, such as cetuximab, which target the EGFR and block the effects of EGFR ligands, such as AREG, can be administered. Patients, however, inevitably develop resistance to cetuximab, either by acquiring KRAS mutations or via non-genetic microenvironmental changes. Here we show that nutrient stress in several CRC cell lines causes the release of AREG-carrying Rab11a-exosomes. We demonstrate that while soluble AREG has no effect, much lower levels of AREG bound to Rab11a-exosomes from cetuximab-resistant KRAS-mutant HCT116 cells, can suppress the effects of cetuximab on KRAS-wild type Caco-2 CRC cells. Using neutralising anti-AREG antibodies and an intracellular EGFR kinase inhibitor, we show that this effect is mediated via AREG activation of EGFR, and not transfer of activated KRAS. Therefore, presentation of AREG on Rab11a-exosomes affects its ability to compete with cetuximab. We propose that this Rab11a-exosome-mediated mechanism contributes to the establishment of resistance in cetuximab-sensitive cells and may explain why in cetuximab-resistant tumours only some cells carry mutant KRAS.
dc.description.confidentialfalse
dc.edition.editionJun 2024
dc.identifier.citationMason JD, Marks E, Fan SJ, McCormick K, Wilson C, Harris AL, Hamdy FC, Cunningham C, Goberdhan DCI. (2024). Stress-induced Rab11a-exosomes induce amphiregulin-mediated cetuximab resistance in colorectal cancer. Journal of Extracellular Vesicles. 13. 6.
dc.identifier.doi10.1002/jev2.12465
dc.identifier.eissn2001-3078
dc.identifier.elements-typejournal-article
dc.identifier.issn2001-3078
dc.identifier.numbere12465
dc.identifier.urihttps://mro.massey.ac.nz/handle/10179/70064
dc.languageEnglish
dc.publisherWiley Periodicals LLC on behalf of International Society for Extracellular Vesicles
dc.publisher.urihttps://isevjournals.onlinelibrary.wiley.com/doi/10.1002/jev2.12465
dc.relation.isPartOfJournal of Extracellular Vesicles
dc.rights(c) 2024 The Author/s
dc.rightsCC BY 4.0
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectAREG
dc.subjectcetuximab
dc.subjectcolorectal cancer
dc.subjectextracellular vesicle
dc.subjectEGFR
dc.subjectRab11a-exosome
dc.titleStress-induced Rab11a-exosomes induce amphiregulin-mediated cetuximab resistance in colorectal cancer
dc.typeJournal article
pubs.elements-id489397
pubs.organisational-groupCollege of Health
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