ATG9A loss confers resistance to trastuzumab via c-Cbl mediated Her2 degradation

Nunes, Joao, Zhang, Hua, Angelopoulos, Nicos ORCID: https://orcid.org/0000-0002-7507-9177, Chhetri, Jyoti, Osipo, Clodia, Grothey, Arnhild, Stebbing, Justin and Giamas, Georgios 2016. ATG9A loss confers resistance to trastuzumab via c-Cbl mediated Her2 degradation. Oncotarget 7 (19) , pp. 27599-27612. 10.18632/oncotarget.8504

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Abstract

Acquired or de novo resistance to trastuzumab remains a barrier to patient survival and mechanisms underlying this still remain unclear. Using stable isotope labelling by amino acids in cell culture (SILAC)-based quantitative proteomics to compare proteome profiles between trastuzumab sensitive/resistant cells, we identified autophagy related protein 9A (ATG9A) as a down-regulated protein in trastuzumab resistant cells (BT474-TR). Interestingly, ATG9A ectopic expression markedly decreased the proliferative ability of BT474-TR cells but not that of the parental line (BT474). This was accompanied by a reduction of Her2 protein levels and AKT phosphorylation (S473), as well as a decrease in Her2 stability, which was also observed in JIMT1 and MDA-453, naturally trastuzumab-resistant cells. In addition, ATG9A indirectly promoted c-Cbl recruitment to Her2 on T1112, a known c-Cbl docking site, leading to increased K63 Her2 polyubiquitination. Whereas silencing c-Cbl abrogated ATG9A repressive effects on Her2 and downstream PI3K/AKT signaling, its depletion restored BT474-TR proliferative rate. Taken together, our findings show for this first time that ATG9A loss in trastuzumab resistant cells allowed Her2 to escape from lysosomal targeted degradation through K63 poly-ubiquitination via c-Cbl. This study identifies ATG9A as a potentially druggable target to overcome resistance to anti-Her2 blockade. Keywords: breast cancer, trastuzumab, resistance, ATG9A, SILAC

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Medicine
Publisher:	Impact Journals
ISSN:	1949-2553
Date of First Compliant Deposit:	29 July 2020
Date of Acceptance:	18 March 2016
Last Modified:	05 May 2023 22:46
URI:	https://orca.cardiff.ac.uk/id/eprint/133814

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